KDIGO CLINICAL PRACTICE GUIDELINE FOR LIPID … · Suppl Table 1: Summary table of RCT examining the effect of exercise in CKD 5HD patients [continuous outcomes] Suppl Table 2: Summary

KDIGO CLINICAL PRACTICE GUIDELINE FOR LIPID MANAGEMENT IN CHRONIC KIDNEY DISEASE

Supplemental Tables November 2013

Suppl Table 1: Summary table of RCT examining the effect of exercise in CKD 5HD patients [continuous outcomes] Suppl Table 2: Summary table of RCT examining low vs. moderate protein diet in CKD patients without DM [categorical outcomes] Suppl Table 3: Summary table of RCT examining low vs. moderate protein diet in CKD patients without DM [continuous outcomes] Suppl Table 4: Summary table of RCT examining statin therapy vs. lifestyle modification in kidney transplant recipients without DM

[categorical outcomes]

Suppl Table 5: Summary table of RCT examining statin therapy vs. lifestyle modification in kidney transplant recipients without DM [continuous outcomes]

Suppl Table 6: Summary table of RCT examining statin therapy vs. usual care in patients with CKD without DM [categorical outcomes] Suppl Table 7: Summary table of RCT examining statin therapy vs. usual care in patients with CKD without DM [continuous outcomes] Suppl Table 8: Summary table of RCTs of statins vs. placebo in patients with CKD with and without DM [categorical outcomes] Suppl Table 9: Summary table of RCTs of statins vs. placebo in various stages of CKD with and without DM [continuous outcomes] Suppl Table 10: Evidence profile of RCTs examining the effect of statins vs. placebo in patients with CKD with and without DM Suppl Table 11: Summary table of RCTs of statins vs. placebo in dialysis patients with and without DM [categorical outcomes] Suppl Table 12: Summary table of RCTs of statins vs. placebo in dialysis patients with and without DM [continuous outcomes] Suppl Table 13: Evidence profile of RCTs examining the effect of statins vs. placebo in dialysis patients with and without DM Suppl Table 14: Summary table of RCT examining statin vs. placebo in patients with ADPKD [continuous outcomes] Suppl Table 15: Summary table of RCT examining simvastatin/ezetimibe combination vs. simvastatin/placebo in CKD patients without

DM [categorical outcomes]

Suppl Table 16: Summary table of RCT examining simvastatin/ezetimibe combination vs. simvastatin/placebo in CKD patients without DM [continuous outcomes]

Suppl Table 17: Summary table of RCT of statin + ezetimibe vs. placebo in CKD patients [categorical outcomes] Suppl Table 18: Summary table of RCT examining the effect of dose of atorvastatin in CKD patients with DM [categorical outcomes] Suppl Table 19: Drug interactions Suppl Table 20: Effects of grapefruit juice on statin pharmacokinetics and recommendations Suppl Table 21: Patients on statin + fibrate therapy reporting any adverse event Suppl Table 22: Patients receiving statin + fibrate therapy reporting other individual adverse events Suppl Table 23: Patients on statin + fibrate therapy reporting treatment related adverse events Suppl Table 24: Patients on statin + fibrate therapy discontinuing due to adverse events Suppl Table 25: Patients on statin + fibrate therapy with increased ALT or AST Suppl Table 26: Patients on statin + fibrate therapy with increased CK Suppl Table 27: Patients on statin + fibrate therapy with increased serum creatinine Suppl Table 28: Patients receiving statin + fibrate therapy reporting rhabdomyolysis Suppl Table 29: Summary table of RCTs of statin vs. placebo in kidney transplant patients [categorical outcomes] Suppl Table 30: Summary table of RCTs of statin vs. placebo in kidney transplant patients [continuous outcomes] Suppl Table 31: Evidence profile of RCTs examining the effect of statins vs. placebo in kidney transplant recipients Suppl Table 32: Summary table of RCTs of statins vs. placebo in children with CKD without DM [continuous outcomes]

3

Supplemental Table 1: Summary table of RCT examining the effect of exercise in CKD 5HD patients [continuous outcomes]

Outcome (Units)

Author, Year Country

Ref #

Duration Outcome

measurement (Treatment)

Description No. Analyzed (Enrolled) Baseline Results (Lipids)

P value Quality

Intervention Control Intervention Control GFR or SCr Proteinuria Baseline

Intervention (Control)

Final Intervention

(Control)

∆ Intervention

(Control) Net ∆

(95% CI)

Lipid levels

∆Total cholesterol, mmol/L

van Vlsteren 2005 The Netherlands1

3 mo (3 mo)

Exercise program Control 53

(60) 43

(43) CKD 5HD nd 4.6 (4.7)

4.6 (4.6)

0 (-0.1) 0.1 NS Good

Supplemental Table 2: Summary table of RCT examining low vs. moderate protein diet in CKD patients without DM [categorical outcomes]

Outcome Author,

Year Country

Ref #

Duration Outcome


Description No. Analyzed (Enrolled) Baseline Results

P value Quality

Intervention Control Intervention Control GFR DM (%)

TC LDL HDL Tg Events No. (%)

Intervention [Control]

RR/OR/HR (95% CI)1 mg/dL

Mortality

All-cause mortality

Cianciaruso 2009 Italy2

4 y (3 y)

Low-protein diet

Moderate-protein diet

212 (212)

211 (211)

16 (17)

mL/min/ 1.73 m2

11 (13) nd 125

(124) nd nd 23 (11%) [25 (12%)]

HR 1.12 (0.64, 1.99) nd Fair

ESRD Cianciaruso 2009 Italy2

4 y (3 y)

Low-protein diet


212 (212)

211 (211)

16 (17)

mL/min/ 1.73 m2

11 (13) nd 125

(124) nd nd 42 (20) [41 (19)]

HR 1.00 (0.65, 1.55) nd Fair

1 Adjusted for age, sex, comorbidity score index, and basal estimated glomerular filtration rate; as well as time-variant covariates including estimated glomerular filtration rate, protein intake, serum phosphate level, therapy with erythropoiesis-stimulating agents, and therapy with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both.

4

Supplemental Table 3: Summary table of RCT examining low vs. moderate protein diet in CKD patients without DM [continuous outcomes]

Outcome Author, Year

Country Ref #

Duration Outcome


Description No. Analyzed (Enrolled) Baseline Results (Lipids) P

value Quality Intervention Control Intervention Control GFR DM

(%) Baseline


Final Intervention

(Control)

∆ Intervention

(Control)

Net ∆ (95% CI)

Lipid levels

∆LDL, mg/dL

Cianciaruso 2009 Italy2

6 mo (3 y)

Low-protein diet


206 (212)

198 (211)

16 (17)

mL/min/ 1.73 m2 11

(13) 125

(124)

118 (122)

-7 (-2)

-5 (-13, 3) NS Fair

1 y (3 y)

199 (212)

191 (211)

118 (120)

-7 (-4)

-3 (-10, 5) NS Fair

2 y (3 y)

189 (212)

187 (211)

116 (115)

-9 (-9)

0 (-7, 7) NS Fair

2 y (3 y)

181 (212)

178 (211)

111 (123)

-14 (-1)

-13 (-21, -5) 0.001 Fair

3 y (3 y)

167 (212)

164 (211)

110 (121)

-15 (-3)

-12 (-20, -4) 0.002 Fair

3 y (3 y)

146 (212)

147 (211)

118 (124)

-7 (0)

-7 (-15, 1)

NS (0.07) Fair

4 y (3 y)

132 (212)

139 (211)

112 (121)

-13 (3)

-10 (-17, 2) 0.012 Fair

4 y (3 y)

127 (212)

124 (211)

113 (111)

-12 (-13)

1 (-7, 9) NS Fair

5

Supplemental Table 4: Summary table of RCT examining statin therapy vs. lifestyle modification in kidney transplant recipients without DM [categorical outcomes]


Country Ref #

Duration Outcome



P value Quality

Intervention Control Intervention Control GFR or SCr DM (%)



RR/OR/HR (95% CI) (mg/dL)

CV events

Focal cerebellar infarctions

Nart 2009 Turkey3

4 y (4 y)

Fluvastatin 40 mg

NCEP modified Step 1

diet

90 (90)

53 (53)

GFR 71.3 (69.7) mL/min

SCr 1.32 (1.43) mg/dL

nd 231 (187)

135 (99)

63 (56)

170 (139)

2 (2%) [0 (0%)] nd nd Fair

* Results are for adjusted analysis if provided. If unadjusted results are different please annotate. Supplemental Table 5: Summary table of RCT examining statin therapy vs. lifestyle modification in kidney transplant recipients without DM [continuous outcomes]

Outcome Author,

Year Country

Ref #

Duration Outcome



P value Quality


Baseline Intervention

(Control)

Final Intervention

(Control)

∆ Intervention

(Control) Net ∆

(95% CI)

Lipid levels

∆LDL, mg/dL

Nart 2009 Turkey3

1 y (4 y)

Fluvastatin 40 mg

NCEP modified Step 1

diet

90 (90)

53 (53)

GFR 71.3 (69.7)

mL/min SCr 1.32 (1.43) mg/dL

nd

135 (99.2)

115.6 (96.2)

-18.9 (-3.0) -15.9 <0.000 Fair

4 y (4 y)

123.4 (101.3)

-11.1 (+2.1) -13.2 <0.000 Fair

∆HDL, mg/dL

1 y (4 y) 63

(56)

53.2) (49.2)

-9.7 (-6.5) -3.2 NS Fair

4 y (4 y)

48.9 (46.1)

-14.0 (-9.6) -4.4 NS Fair

∆Triglycerides, mg/dL

1 y (4 y) 170

(139)

169.7 (143.4)

-0.6 (+4.7) -5.3 0.035 Fair

4 y (4 y)

163.0 (145.3)

-7.3 (+6.6) -0.7 NS Fair

∆Total cholesterol, mg/dL

1 y (4 y) 231.2

(187.3)

202.7 (172.7)

-28.5 (-14.6) -13.9 0.00 Fair

4 y (4 y)

206.0 (177.7)

-25.2 (-9.6) -15.6 0.00 Fair

6

Supplemental Table 6: Summary table of RCT examining statin therapy vs. usual care in patients with CKD without DM [categorical outcomes]


Country Ref #

Duration Outcome



P value Quality





Composite outcome ESRD or Halving of GFR

ALLHAT (CKD subgp) Rahman 2008 Multi4

5 y (5 y)

Pravastatin 40 mg/d

Usual care

779 (779)

778 (778)

GFR 50.8 (50.6)

mL/min/1.73 m2 32

(30) 226

(224) 147

(145) 46

(46)2 165

(164)

52 (7) [50 (6)]

RR 0.97 (0.66, 1.43) nd Good3

ESRD or 25% decline in GFR

156 (20) [154 (20])

RR 0.98 (0.79, 1.22) nd Good4

Kidney function

ESRD ALLHAT (CKD subgp) Rahman 2008 Multi4

5 y (5 y)

Pravastatin 40 mg/d

Usual care

779 (779)

778 (778)

GFR 50.8 (50.6)

mL/min/1.73 m2 nd 226

(224) 147

(145) 46

(46)5 165

(164) 32 (4) [31 (4)]

RR 1.05 (0.64, 1.73) nd Good6

* Results are for adjusted analysis if provided. If unadjusted results are different please annotate.

2 Estimated from graph 3 Study is graded “Good” however consider downgrading in EP due to the fact that “there was no significant interaction of baseline eGFR and treatment group”. 4 Study is graded “Good” however consider downgrading in EP due to the fact that “there was no significant interaction of baseline eGFR and treatment group”. 5 Estimated from graph 6 Study is graded “Good” however consider downgrading in EP due to the fact that “there was no significant interaction of baseline eGFR and treatment group”.

7

Supplemental Table 7: Summary table of RCT examining statin therapy vs. usual care in patients with CKD without DM [continuous outcomes]

Outcome Author,

Year Country

Ref #

Duration Outcome



P value Quality Intervention Control Intervention Control GFR or SCr DM

(%) Baseline


Final Intervention

(Control)

∆ Intervention

(Control)

Net ∆ (95% CI)

Lipid levels ∆Total cholesterol, mg/dL

ALLHAT (CKD subgp) Rahman 2008 Multi4

5 y (5 y)

Pravastatin 40 mg/d

Usual care

779 (779)

778 (778)

GFR 50.8 (50.6)

mL/min/1.73 m2 32

(30)

226 (224)

178 (198)7

-48.2 (-26.1) -22.1 nd Good8

∆HDL, mg/dL 46 (46)9

56 (38)10

+10 (-8) 18 nd Good11

7 Estimated from graph 8 Study is graded “Good” however consider downgrading in EP due to the fact that “there was no significant interaction of baseline eGFR and treatment group”. 9 Estimated from graph 10 Estimated from graph 11 Study is graded “Good” however consider downgrading in EP due to the fact that “there was no significant interaction of baseline eGFR and treatment group”.

8

Supplemental Table 8: Summary table of RCTs of statins vs. placebo in patients with CKD with and without DM [categorical outcomes]

Outcome Author,

Year Country

Ref #

Duration Outcome


Description No. Analyzed (Enrolled) Baseline Results P

value Quality Intervention Control Intervention Control GFR or

SCr DM (%)



RR/OR/HR (95% CI) mg/dL

CKD with DM Composite outcomes Coronary heart disease death, nonfatal MI, CABG, or PTCA (primary)

CARE, LIPID, WOSCOPS (CKD subgp) Tonelli 2005 Multi5

5 y (5 y) Pravastatin Placebo 571

(571)

eGFR 58 ml/min/1.73

m2 SCr 1.3 mg/dL

100 (100) 213 140 36 181 nd

HR 0.7512 (0.57, 0.98) <0.05 Fair

Coronary heart disease death, nonfatal MI, CABG, PTCA, or stroke

HR 0.7913 (0.62, 1.03)

NS (0.06) Fair

Coronary heart disease death or nonfatal MI

HR 0.8414 (0.60, 1.18) NS Fair

Mortality

All-cause mortality



(571)

eGFR 58 ml/min/1.73

m2 SCr 1.3 mg/dL

100 (100) 213 140 36 181 nd HR 0.9815

(0.69, 1.39) NS Fair

12 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB 13 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB 14 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB 15 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB

9

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




All cause mortality

CARDS (CKD subgp) Colhoun, 2009 UK Ireland6

4 y (4 y) Atorvastatin Placebo 482

(482) 488

(488)

eGFR 53.5

(54.1) mL/min/1.

73 m2

100 (100)

210 (212)

120 (120)

56 (56)

≤600 (≤60

0) 27 (6%) [30 (6%)]

HR 0.8616 (0.51, 1.45) NS Good

CV events

CABG or PTCA CARE, LIPID, WOSCOPS (CKD subgp) Tonelli 2005 Multi5


(571)

eGFR 58 ml/min/1.73

m2 SCr 1.3 mg/dL

100 (100) 213 140 36 181 nd

HR 0.6917 (0.47, 1.01)

NS (0.06) Fair

Any stroke HR 1.1218 (0.63,1.97) NS Fair

Major CV disease CARDS

(CKD subgp) Calhoun, 2009 UK Ireland6


(482) 488

(488)

eGFR 53.5

(54.1) mL/min/1.

73 m2

100 (100)

210 (212)

120 (120)

56 (56)

≤600 (≤60

0)

25 (5%) [42 (9%)]

HR 0.5719 (0.35, 0.94) 0.02 Good

Stroke 6 (1%) [15 (3%)]

HR 0.3820 (0.15, 0.99) 0.04 Good

Coronary heart disease

18 (4%) [27 (6%)]

HR 0.6521 (0.36, 1.17) NS Good

Coronary revascularization

5 (1%) [12 (2%)]

HR 0.4022 (0.14, 1.15)

NS (0.07) Good

CKD without DM Composite outcomes

16 Adjusted for age, sex and treatment group 17 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB 18 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB 19 Adjusted for age, sex and treatment group 20 Adjusted for age, sex and treatment group 21 Adjusted for age, sex and treatment group 22 Adjusted for age, sex and treatment group

10

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




Nonfatal MI, nonfatal stroke, hospital stay for unstable angina, arterial revascularization, or confirmed CV death (primary)

JUPITER Ridker 2010 Multi7

2 y (2 y)

Rosuvastatin Placebo 1638

(1638) 1629

(1629) eGFR 56 ml/min/1.

73 m2 0

(0) 189 109 49 130

40 (2%) [71 (4%)]

HR 0.55 (0.38, 0.82) 0.002 Good

MI, stroke, or confirmed CV death

24 (2%) [40 (3%)]

HR 0.59 (0.36, 0.99) 0.04 Good

Nonfatal MI, nonfatal stroke, hospital stay for unstable angina, arterial revascularization, or confirmed CV death and all-cause mortality

64 (4%) [114 (7%)]

HR 0.55 (0.41, 0.75) 0.0001 Good

Nonfatal MI, nonfatal stroke, hospital stay for unstable angina, arterial revascularization, or confirmed CV death and all-cause mortality and venous thromboembolism

69 (4%) [127 (8%)]

HR 0.53 (0.40, 0.71)

<0.0001 Good

11

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




Coronary heart disease death, nonfatal MI, CABG, or PTCA (primary)


Median 5 y

(5 y) Pravastain Placebo 4099

(4099)

eGFR 56.5

ml/min/1.73 m2

SCr 1.3 mg/dL

0 (0) 224 153 38 161 nd

HR 0.7723 (0.68, 0.87) <0.05 Fair

Coronary heart disease death, nonfatal MI, CABG, PTCA, or stroke

HR 0.8024 (0.71, 0.90) <0.05 Fair

Coronary heart disease death or nonfatal MI

HR 0.8525 (0.73, 1.00) 0.05 Fair

First primary CV event including cardiac death, nonfatal MI, resuscitated cardiac arrest, cardiac revascularization or unstable angina requiring hospitalization

ALLIANCE (CKD subgp) Koren 2009 US8

5 y (5 y) Atorvastatin Usual

care 286

(286) 293

(293)

eGFR 51.3

(51.1) mL/min/1.

73 m2

30 (26)

228 (227)

148 (146)

40 (40)

200 (207)

78 (27%) [105 (36%)]

HR 0.72 (0.54, 0.97) 0.02 Fair

Nonfatal MI or cardiac death

32 (11%) [54 (18%)]

HR 0.55 (0.35, 0.85) 0.008 Fair

23 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB 24 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB 25 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB

12

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




CV mortality and hospitalization for CV morbidity (primary)

PREVEND IT Asselbergs 2004 Netherlands9


(433) 431

(431) SCr 91 (90)

µmol/L 3

(2)

5.8 (5.8)

mmol/L

4.1 (4.0) mmol

/L

1.0 (1.0) mmol/L

1.4 (1.3) mmol

/L

22 (5%) [25 (6%)]

HR 0.87 (0.49, 1.57) NS Fair

Cardiac death or MI

LIPS (CKD subgp) Lemos 2005 Multi10

4 y (4 y) Fluvastatin Placebo 150

(150) 160

(160)

SCr 1.33 mg/dL

CrCl <47 mL/min

Total 12 200 131 39 150

7 (5%) [13 (8%)]

RR 0.57 (0.24, 1.40) NS Fair26

All cause death or MI

7 (5%) [13 (8%)]

RR 0.57 (0.24, 1.40) NS Fair27

Unstable angina, fatal and nonfatal MI, and sudden death

AFCAPS/TexCAPS (CKD subgp) Kendrick 2010 US11

5 y (5 y) Lovastatin Placebo 145

(145) 159

(159)

GFR 53 (53)

mL/min/1.73 m2

SCr 1.4 (1.4)

mg/dL

1 (2)

224 (220)

151 (151)

39 (39)

177 (168)

5 (3.4%) 17 (7.5%)

RR 0.32 (0.10, 1.11)

NS (0.06) Good28

Mortality

All-cause mortality


2 y (2 y)


(1638) 1629

(1629) eGFR 56 ml/min/1.

73 m2 0

(0) 189 109 49 130 34 (2%) [61 (4%)]

HR 0.56 (0.37, 0.85) 0.005 Good

26 Study graded “Fair” due to unbalance in baseline characteristics. No info on treatment vs. placebo among the 310 renal impairment patients. Consider downgrading further in EP due to being unable to locate interaction results. 27 Study graded “Fair” due to unbalance in baseline characteristics. No info on treatment vs. placebo among the 310 renal impairment patients. Consider downgrading further in EP due to being unable to locate interaction results. 28 Study is graded “Good”, however consider downgrading in EP due to the fact that for all clinical events, the effects of lovastatin did not differ significantly between subgroups with and without CKD(P>0.1) for all interaction tests.

13

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




All-cause mortality


5 y (5 y) Pravastain Placebo 4099

(4099)

eGFR 56.5

ml/min/1.73 m2

SCr 1.3 mg/dL

0 (0) 224 153 38 161 nd HR 0.9729

(0.82, 1.15) NS Fair

All-cause mortality

ALLIANCE (CKD subgp) Koren 2009 US8


care 286

(286) 293

(293)

eGFR 51.3

(51.1) mL/min/1.

73 m2

30 (26)

228 (227)

148 (146)

40 (40)

200 (207)

47 (16%) [59 (20%)]

RR 0.82 (0.58, 1.15)30

NS Fair

All-cause mortality

PREVEND IT Asselbergs 2005 Netherland9

s


(433) 431

(431) SCr 91 (90)

µmol/L 3

(2)

5.8 (5.8)

mmol/L

4.1 (4.0) mmol

/L

1.0 (1.0) mmol/L

1.4 (1.3) mmol

/L

6 (1%) [4 (1%)]

RR 1.49 (0.42-5.25)31

NS Fair

All-cause mortality

LIPS (CKD subgp) Lemos 2005 Multi10


(150) 160

(160)

SCr 1.33 mg/dL

CrCl <47 mL/min

Total 12 200 131 39 150

3 (2%) [3 (2%)]

RR 1.07 (0.22, 5.20) NS Fair32

Noncardiac death

0 (0%) [0 (0%)] -- nd Fair33

29 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB 30 Calculated by the ERT 32 Study graded “Fair” due to unbalance in baseline characteristics. No info on treatment vs. placebo among the 310 renal impairment patients. Consider downgrading further in EP due to being unable to locate interaction results. 33 Study graded “fair” due to unbalance in baseline characteristics. No info on treatment vs. placebo among the 310 renal impairment patients. Consider downgrading further in EP due to being unable to locate interaction results.

14

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




All-cause mortality (primary)

4S (CKD subgp) Chonchol 2007 Scandinavian countries12

5 y (5 y) Simvastatin Placebo 1143

(1143) 1171

(1171)

GFR 65.2 (65.2)

mL/min)34 SCr 1.15

(1.14) mg/dL

5 (4)

261 (261)

189 (189)

46 (46)

131 (134)

Total 246 (11%)

HR 0.69 (0.54, 0.89) nd Good35

Total mortality

MEGA (CKD subgp) Nakamura 2009 Japan13

5 y (5 y)

Pravastatin + NCEP

Step 1 Diet

NCEP Step 1 Diet

1462 (1462)

1516 (1516)

GFR 52.6 (52.5)

mL/min/m2

Total 19 6.3

mmol/L

4.0 mmol

/L

1.5 mmol/L

1.5 mmol

/L 16 (1%) [34 (2%)]

HR 0.49 (0.27, 0.89) 0.02 Fair36

CV Mortality Death from CHD or nonfatal MI (primary)

CARE (CKD subgp) Tonelli 2003 US & Canada14


(844) 867

(867)

CrCl 61.2 (61.3)

mL/min37 Scr 61.2 (61.3) µmol/L

13 (15)

209 (209)

138 (139)

41 (41)

149 (149)

89 (11%) [126 (15%)]

HR 0.7238 (0.55, 0.95) 0.02 Good

Total mortality 86 (10%) [111 (13%)]

HR 0.8139 (0.61, 1.08) NS Good

Cardiac death LIPS (CKD subgp) Lemos 2005 Multi10


(150) 160

(160)

SCr 1.33 mg/dL

CrCl CrCl <47

mL/min

Total 12 200 131 39 150 3 (2%) [3 (2%)]

RR 1.07 (0.22, 5.20) NS Fair40

34 Mild chronic renal insufficiency is defined as eGFR <75 mL/min/1.73m2 (<1.25 mL/s) or creatinine clearance <75 mL/min (1.25 mL/s) 35 Study is graded “Good” however consider downgrading in EP due to inconsistency in interaction test results (P=0.05 for total mortality and P=0.84 for major coronary events). 36 Study is graded “Fair” due to the fact that baseline characteristics by intervention were not provided in the CKD subgroup. Consider downgrading again in EP due to not being able to find interaction results. 37 Mild chronic renal insufficiency is defined as creatinine clearance <75 mL/min 38 Adjusted for age; sex; history of HTN; smoking at baseline; DM; previous CHF; use of ACEi, CCB, β-adrenergic blockers, and aspirin; proteinuria; SBP and DBP; baseline HDL and LDL, cholesterol levels; baseline Tg; serum albumin levels; BSA; and pravastatin use. 39 Adjusted for age; sex; history of HTN; smoking at baseline; DM; previous CHF; use of ACEi, CCB, β-adrenergic blockers, and aspirin; proteinuria; SBP and DBP; baseline HDL and LDL, cholesterol levels; baseline Tg; serum albumin levels; BSA; and pravastatin use. 40 Study graded “Fair” due to unbalance in baseline characteristics. No info on treatment vs. placebo among the 310 renal impairment patients. Consider downgrading further in EP due to being unable to locate interaction results.

15

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




CV mortality



(145) 159

(159)

GFR 53 (53)

mL/min/1.73m2

SCr 1.4 (1.4)

mg/dL

1 (2)

224 (220)

151 (151)

39 (39)

177 (168)

0 (0%) [1 (0.6%)] -- nd Good41

CV mortality



(433) 431

(431) SCr 91 (90)

µmol/L 3

(2)

5.8 (5.8)

mmol/L

4.1 (4.0) mmol

/L

1.0 (1.0) mmol/L

1.4 (1.3) mmol

/L

4 (1%) [4 (1%)] nd nd Fair

CV events

MI


2 y (2 y) Rosuvastatin Placebo 1638

(1638) 1629

(1629) eGFR 56 ml/min/1.

73 m2 0

(0) 189 109 49 130

8 (1%) [20 (1%)]

HR 0.40 (0.17, 0.90) 0.02 Good

Stroke 10 (1%) [14 (1%)]

HR 0.71 (0.31, 1.59) NS Good

Arterial revascularization

19 (1%) [39 (1%)]

HR 0.48 (0.28, 0.83) 0.006 Good

Venous thromboembolism

6 (0.3%) [17 (1%)]

HR 0.34 (0.14, 0.88) 0.02 Good

Major coronary event CARE

Tonelli 2003 US & Canada14


(844) 867

(867)

CrCl 61.2 (61.3)

mL/min42 Scr 61.2 (61.3)

13 (15)

209 (209)

138 (139)

41 (41)

149 (149)

171 (20%) [234 (27%)]

HR 0.7243 (0.59, 0.88) 0.001 Good

Fatal MI or confirmed nonfatal MI

65 (8%) [90 (10%)]

HR 0.7344 (0.52, 1.01)

NS (0.06) Good

41 Study is graded “Good”, however consider downgrading in EP due to the fact that for all clinical events, the effects of lovastatin did not differ significantly between subgroups with and without CKD(P>0.1) for all interaction tests. 42 Mild chronic renal insufficiency is defined as creatinine clearance <75 mL/min 43 Adjusted for age; sex; history of HTN; smoking at baseline; DM; previous CHF; use of ACEi, CCB, β-adrenergic blockers, and aspirin; proteinuria; SBP and DBP; baseline HDL and LDL, cholesterol levels; baseline Tg; serum albumin levels; BSA; and pravastatin use. 44 Adjusted for age; sex; history of HTN; smoking at baseline; DM; previous CHF; use of ACEi, CCB, β-adrenergic blockers, and aspirin; proteinuria; SBP and DBP; baseline HDL and LDL, cholesterol levels; baseline Tg; serum albumin levels; BSA; and pravastatin use.

16

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




CABG or PTCA µmol/L 105 (12%) [153 (18%)]

HR 0.6545 (0.50, 0.83) 0.001 Good

Unstable angina

133 (16%) [142 (16%)]

HR 0.9346 (0.73, 1.18) NS Good

Stroke 29 (3%) [46 (5%)]

HR 0.6247 (0.39, 1.00) 0.051 Good

Major coronary event in subgroup of CKD and proteinuria

255 (255)

268 (268) nd Dipstick

+

nd nd nd nd

65 (26%) [81 (30%)]

Unadjusted absolute reduction

in cumulative incidence

4.7

nd Good

Major coronary event in subgroup with CrCl >75 mL/min

1139 (1139)

1164 (1164)

CrCl >75

mL/min

nd

244 (21%) [315 (27%)]



5.7

nd Good

Major coronary event in subgroup with CrCl ≤75 mL/min

844 (844)

867 (867)

CrCl ≤75

mL/min 171 (20%)

[234 (27%)]



6.7

nd Good

45 Adjusted for age; sex; history of HTN; smoking at baseline; DM; previous CHF; use of ACEi, CCB, β-adrenergic blockers, and aspirin; proteinuria; SBP and DBP; baseline HDL and LDL, cholesterol levels; baseline Tg; serum albumin levels; BSA; and pravastatin use. 46 Adjusted for age; sex; history of HTN; smoking at baseline; DM; previous CHF; use of ACEi, CCB, β-adrenergic blockers, and aspirin; proteinuria; SBP and DBP; baseline HDL and LDL, cholesterol levels; baseline Tg; serum albumin levels; BSA; and pravastatin use. 47 Adjusted for age; sex; history of HTN; smoking at baseline; DM; previous CHF; use of ACEi, CCB, β-adrenergic blockers, and aspirin; proteinuria; SBP and DBP; baseline HDL and LDL, cholesterol levels; baseline Tg; serum albumin levels; BSA; and pravastatin use.

17

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




Major coronary event in subgroup with CrCl 60-75 mL/min

524 (524)

518 (518)

CrCl 60-75

mL/min 103 (20%)

[143 (28%)]



7.9

nd Good

Major coronary event in subgroup with CrCl 50-75 mL/min

719 (719)

736 (736)

CrCl 50-75

mL/min 140 (20%)

[207 (28%)]



8.6

nd Good


320 (320)

349 (349)

CrCl ≤60

mL/min 68 (21%) [91 (26%)]



4.8

nd Good


125 (125)

131 (131)

CrCl ≤50

mL/min 31 (25%) [27 (21%)] -- nd Good

CABG or PTCA CARE, LIPID,

5 y (5 y) Pravastain Placebo 4099

(4099) eGFR 56.5

0 (0) 224 153 38 161 nd HR 0.7248

(0.61, 0.86) <0.05 Fair

48 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB

18

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




Any stroke

WOSCOPS (CKD subgp) Tonelli 2005 Multi5

ml/min/1.73 m2

SCr 1.3 mg/dL

HR 0.9649 (0.71, 1.30) NS Fair

Non-fatal MI ALLIANCE (CKD subgp) Koren 2009 US8


care 286

(286) 293

(293)

eGFR 51.3

(51.1) mL/min/1.

73 m2

30 (26)

228 (227)

148 (146)

40 (40)

200 (207)

17 (6%) [29 (10%)]

HR 0.54 (0.30, 0.99) NS Fair

Stroke 11 (4%) [12 (4%)]

RR 0.94 (0.42, 2.09)50

NS Fair

Cardiac death 17 (6%) [27 (9%)]

RR 0.65 (0.36,1.16)

51 NS Fair

Fatal and non fatal CV events



(145) 159

(159)

GFR 53 (53)

mL/min/1.73 m2

SCr 1.4 (1.4)

mg/dL

1 (2)

224 (220)

151 (151)

39 (39)

177 (168)

8 (6%) [21 (13%)]

RR 0.39 (0.16, 0.93) 0.0352 Good53

Fatal and non fatal MI

2 (1%) [6 (4%)]

RR 0.10 (0.01, 1.32)

NS (0.08) Good54

Major coronary events

4S (CKD subgp) Chonchol


(1143) 1171

(1171) GFR 65.2

(65.2) mL/min)55

5 (4)

261 (261)

189 (189)

46 (46)

131 (134)

Total (24%)

HR 0.67 (0.56, 0.79) nd Good56

49 Hazards ratio have been adjusted for age; SBP; HDL; LDL; triglyceride; an indicator for trial (CARE, LIPID, or WOSCOPS); current smoking status; history of stroke; history of coronary disease; insulin dependence; and baseline use of aspirin, β blockers, ACEi, and CCB 50 Calculated by the ERT 51 Calculated by the ERT 52 Fully adjusted model 53 Study is graded “Good”, however consider downgrading in EP due to the fact that for all clinical events, the effects of lovastatin did not differ significantly between subgroups with and without CKD(P>0.1) for all interaction tests. 54 Study is graded “Good”, however consider downgrading in EP due to the fact that for all clinical events, the effects of lovastatin did not differ significantly between subgroups with and without CKD(P>0.1) for all interaction tests. 55 Mild chronic renal insufficiency is defined as eGFR <75 mL/min/1.73m2 (<1.25 mL/s) or creatinine clearance <75 mL/min (1.25 mL/s) 56 Study is graded “Good” however consider downgrading in EP due to inconsistency in interaction test results (P=0.05 for total mortality and P=0.84 for major coronary events).

19

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




Nonfatal MI 2007 Scandinavian countries12

SCr 1.15 (1.14) mg/dL

nd HR 0.65 (0.55, 0.78) nd Good57


nd HR 0.62 (0.49, 0.77) nd Good58

CV events



(433) 431

(431) SCr 91 (90)

µmol/L 3

(2)

5.8 (5.8) mmol

/L

4.1 (4.0)

mmol/L

1.0 (1.0) mmol/L

1.4 (1.3) mmol

/L

18 (4%) [21 (5%)]

nd nd Fair

Stroke

MEGA (CKD subgp) Nakamura 2009 Japan13

5 y (5 y)

Pravastatin + NCEP

Step 1 Diet

NCEP Step 1 Diet

1462 (1462)

1516 (1516)

GFR 52.6 (52.5)

mL/min/m2

Total 19 6.3 mmol/L

4.0 mmol/L

1.5 mmol/L

1.5 mmol

/L 8 (1%)

[29 (2%)] HR 0.27

(0.12, 0.59) 0.01 Fair59

Kidney function

Doubling of SCr JUPITER Ridker 2010 Multi7

2 y (2 y)


(1638) 1629

(1629) eGFR 56 ml/min/1.

73 m2 0

(0) 189 109 49 130 3 (0.2%) [0 (0%)] nd nd Good

↓≥25% MDRD-eGFR in patients with mild CKD


Median 5 y

(5 y) Pravastain Placebo 6479

(6479) 6364

(6364)

eGFR 73.8 (73.8)

mL/min/1.73 m2

SCr 1.08 (1.08) mg/dL

6 (6)

236 (236)

163 (163)

40 (40)

160 (158)

nd (10%) [nd (11%)]

RR 0.94 (0.85, 1.03) NS Fair

Acute renal failure in patients with mild CKD

nd (0.2%) [nd [0.5%)]

RR 0.42 (0.22, 0.78) 0.006 Fair

57 Study is graded “Good” however consider downgrading in EP due to inconsistency in interaction test results (P=0.05 for total mortality and P=0.84 for major coronary events). 58 Study is graded “Good” however consider downgrading in EP due to inconsistency in interaction test results (P=0.05 for total mortality and P=0.84 for major coronary events). 59 Study is graded “Fair” due to the fact that baseline characteristics by intervention were not provided in the CKD subgroup. Consider downgrading again in EP due to not being able to find interaction results.

20

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




eGFR ≤60 ml/min/1.73m2 in patients with mild CKD

nd (27%) [nd [29%)]

RR 0.95 (0.90, 1.00)

NS (0.06) Fair

↓≥25% CG-eGFR in patients with mild CKD

<6479 (<6479)

<6364 (<6364) nd 6

(6) nd nd nd nd nd (9%) [nd (10%)]

RR 0.88 (0.78, 0.91) 0.03 Fair

↓eGFR ≥25%



(145) 159

(159)

GFR 53 (53)

mL/min/1.73 m2

SCr 1.4 (1.4) mg/dL

1 (2)

224 (220)

151 (151)

39 (39)

177 (168)

4% [3%] nd NS Good60

↓GFR≥25%

4S (CKD subgp) Huskey 2009 Scandinavian countries16


(199) 210

(210)

GFR 55 (55)

mL/min/1.73 m261

4 (1)

265 (265

) 192

(191) 47

(48) 133

(134) 5 (3%)

[13 (6%)] OR 0.21

(0.05, 0.94) 0.04 Good62

60 Study is graded “Good”, however consider downgrading in EP due to the fact that for all clinical events, the effects of lovastatin did not differ significantly between subgroups with and without CKD(P>0.1) for all interaction tests. 61 Mild chronic renal insufficiency is defined as eGFR <60 mL/min/1.73m2 62 Study is graded “Good” however consider downgrading in EP due to inconsistency in interaction test results (P=0.05 for total mortality and P=0.84 for major coronary events).

21

Supplemental Table 9: Summary table of RCTs of statins vs. placebo in various stages of CKD with and without DM [continuous outcomes]

Outcome (Units)


Ref #

Duration Outcome




SCr DM (%)


(Control)

Final Intervention

(Control)

∆ Intervention

(Control) Net ∆

(95% CI)

CKD without DM Lipid levels Median LDL, mg/dL


2 y (2 y)


(1638) 1629

(1629)

eGFR 56

ml/min/1.73 m2

0 (0)

189 (189)

55 (108)

-134 (-81) -53 <0.001 Good

Median HDL, mg/dL

49 (49)

53 (50)

4 (1) 3 nd Good

Median Triglycerides, mg/dL

130 (130)

99 (129)

-31 (-1) -30 nd Good

∆LDL, mg/dL

CARE Tonelli 200317 US & Canada


(345) 345

(345)

GFR 53.2

(52.5) mL/min/1.73 m2

SCr 1.4 (1.4) mg/dL

14 (17)

139.5 (138.7) nd -41

(nd) nd nd Fair

Total cholesterol, mg/dL

210.0 (209.9) nd -41

(nd) nd nd Fair

%∆Total cholesterol, mg/dL ALLIANCE

(CKD subgp) Koren 2009 US8


care 271

(286) 158

(293)

eGFR 51.3

(51.1) mL/min/1.73 m2

30 (26)

228.4 (227.0) nd -24

(-15)63 -9 <0.001 Fair

∆LDL, mg/dL 148.2 (146.0)

92.2 (106.1)

-34.5 (-24.2) -10.3 <0.001 Fair

%∆HDL , mg/dL 40.2 (40.3) nd +4

(+8)64 4 0.1 Fair %∆Triglycerides , mg/dL

200.3 (207.3) nd -8

(-4)65 -4 0.5 Fair ∆Total cholesterol, mmol/L


4 y (4 y) Pravastatin Placebo

376 (433)

382 (431) SCr 91

(90) µmol/L

3 (2)

5.8 (5.8)

mmol/L

4.8 (5.6)

mmol/L -1

(-0.2) -0.8 <0.0566 Fair

∆LDL cholesterol, mmol/L

375 (433)

379 (431)

4.1 (4.0)

mmol/L

3.1 (3.9)

mmol/L -1

(-0.1) -0.9 <0.0567 Fair

63 Estimated from figure 64 Estimated from figure 65 Estimated from figure 66 Results of ∆ in total cholesterol from baseline to 3 months, 1 year, 2 years and 3 years was also statistically significant. 67 Results of ∆ in LDL from baseline to 3 months, 1 year, 2 years and 3 years was also statistically significant.

22

Outcome (Units)


Ref #

Duration Outcome




SCr DM (%)


(Control)

Final Intervention

(Control)

∆ Intervention

(Control) Net ∆

(95% CI)

∆Total cholesterol, mg/dL AFCAPS/Tex

CAPS (CKD subgp) Kendrick 2010 US11


(145) 159

(159)

GFR 53 (53)

mL/min/1.73 m2

SCr 1.4 (1.4)

mg/dL

1 (2)

224 (220) nd -20%

(+1.5%) -18.5% nd Good68

∆HDL, mg/dL 39 (39) nd +7.4%

(+1.1%) +6.3% nd Good69

∆LDL, mg/dL 151 (151) nd -27%

(+1.9%) -25.1% nd Good70


177 (168) nd -15%

(+4.2%) -10.8% nd Good71

∆Total cholesterol, mg/dL 4S (CKD

subgp) Chonchol 2007 Scandinavian countries12


(1143) 1171

(1171)

GFR 65.2

(65.2) mL/min)

72 SCr 1.15

(1.14) mg/dL

5 (4)

261 (261)

233 (261)

-28% (0%) -28% nd Good73

∆HDL, mg/dL 46 (46)

52 (43)

+6% (-3%) +3% nd Good74

∆LDL, mg/dL 189 (189)

151 (186)

-38% (+2%) -36% nd Good75


131 (134)

115 (136)

-16% (+2%) -14% nd Good76

68 Study is graded “Good”, however consider downgrading in EP due to the fact that for all clinical events, the effects of lovastatin did not differ significantly between subgroups with and without CKD(P>0.1) for all interaction tests. 69 Study is graded “Good”, however consider downgrading in EP due to the fact that for all clinical events, the effects of lovastatin did not differ significantly between subgroups with and without CKD(P>0.1) for all interaction tests. 70 Study is graded “Good”, however consider downgrading in EP due to the fact that for all clinical events, the effects of lovastatin did not differ significantly between subgroups with and without CKD(P>0.1) for all interaction tests. 71 Study is graded “Good”, however consider downgrading in EP due to the fact that for all clinical events, the effects of lovastatin did not differ significantly between subgroups with and without CKD(P>0.1) for all interaction tests. 72 Mild chronic renal insufficiency is defined as eGFR <75 mL/min/1.73m2 (<1.25 mL/s) or creatinine clearance <75 mL/min (1.25 mL/s) 73 Study is graded “Good” however consider downgrading in EP due to inconsistency in interaction test results (P=0.05 for total mortality and P=0.84 for major coronary events). 74 Study is graded “Good” however consider downgrading in EP due to inconsistency in interaction test results (P=0.05 for total mortality and P=0.84 for major coronary events). 75 Study is graded “Good” however consider downgrading in EP due to inconsistency in interaction test results (P=0.05 for total mortality and P=0.84 for major coronary events). 76 Study is graded “Good” however consider downgrading in EP due to inconsistency in interaction test results (P=0.05 for total mortality and P=0.84 for major coronary events).

23

Supplemental Table 10: Evidence profile of RCTs examining the effect of statins vs. placebo in patients with CKD with and without DM

Outcome # of studies

and study design

Total N (treatment)

Methodological quality of studies

per outcome Consistency

across studies

Directness of the evidence

generalizability/ applicability

Other considerations

Summary of findings

Quality of evidence for outcome Qualitative description of effect Importance

of outcome

Composite outcomes

DM MA of 3 RCTs (High)

571 (nd)

Some limitations (-1) NA

Uncertainty about directness

(-1) None

(0) Low Possible benefit from statins in patients with DM

Critical NonDM

MA of 3 RCTs + 5 RCTs

(High) 9423

(2652 + nd) No limitations

(0) No important

inconsistencies (0)


(-1) None

(0) Moderate Benefit from statins in patients without DM

Mortality DM

MA of 3 RCTs + 1 RCT (High)

1541 (482 + nd)

No limitations (0)

No important inconsistencies

(0)


(-1) None

(0) Moderate No difference in patients with DM

Critical NonDM


(High) 14411


(0) Important

inconsistencies (-1)


(-1) None

(0) Low Possible benefit from statins in patients without DM

CV mortality DM 0 RCTs -- -- -- -- -- -- --

Critical NonDM

4 RCTs (High)

3186 (1572)

No limitations (0)

Important inconsistencies

(-1)


(-1) None


CV events DM

MA of 3 RCTs + 1 RCT (High)

1541 (482 + nd)

No limitations (0)


(0)


(-1) None

(0) Moderate Possible benefit from statins for patients with DM

Critical NonDM


(High) 16116


(0) No important

inconsistencies (0)


(-1) None


ESRD DM 0 RCTs -- -- -- -- -- --

-- Critical NonDM 0 RCTs -- -- -- -- -- --

Kidney function (categorical)

DM 0 RCTs -- -- -- -- -- -- --

High NonDM


(High) 18728 (9405)

Some limitations (-1)


(0)


(-1) None


Lipid levels (continuous)

DM 0 RCTs -- -- -- -- -- -- --

Moderate NonDM

6 RCTs (High)

7762 (3918)

No limitations (0)


(0)


(-1) None


Adverse events MA of 3 RCTs

+ 8 RCTs (High)

16256 (5951 + nd) No difference Moderate

Total MA of 3 RCTs

+ 8 RCTs (High)

16256 (5951 + nd)

24


and study design

Total N (treatment)



across studies




Summary of findings

Quality of evidence for outcome Qualitative description of effect Importance

of outcome

Balance of potential benefits and harms: Possible benefit

Quality of overall evidence: Low

25

Supplemental Table 11: Summary table of RCTs of statins vs. placebo in dialysis patients with and without DM [categorical outcomes]

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




Dialysis with DM Composite outcomes Composite of cardiac death, nonfatal MI, or stroke (primary)

4D Wanner 2005 Germany18

4 y (2 y)

Atorvastatin Placebo

619 (619)

636 (636)

CKD 5HD 100 (100)

218 (220)

125 (127)

36 (36)

261 (267)

226 (37%) [243 (38%)]

RR 0.92 (0.77, 1.10) NS Good

Composite of cardiac death, nonfatal MI, or stroke for CRP quartile 1 (≤2.3 mg/L)

4D Krane 2008 Germany19

4 y (2 y)

316 (316)

nd

126

nd nd

60 [50]

HR 1.19 (0.81,1.76) NS Fair

Composite of cardiac death, nonfatal MI, or stroke for CRP quartile 2 (>2.3-≤5 mg/L)

310 (310) 128 50

[56] HR 0.75

(0.50, 1.10) NS Fair

Composite of cardiac death, nonfatal MI, or stroke for CRP quartile 3 (>5-≤12.4 mg/L)

312 (312) 126 52

[78] HR 0.79

(0.55, 1.13) NS Fair

Composite of cardiac death, nonfatal MI, or stroke for CRP quartile 4 (>12.4 mg/L)

311 (311) 122 62

[57] HR 1.06

(0.73, 1.54) NS Fair

Primary outcome in 2nd and 3rd CRP quartiles combined

622 (622) nd nd HR 0.85

(0.65, 1.10) NS Fair

26

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




Major CV event, defined as nonfatal MI, nonfatal stroke, or death from CV causes

AURORA Fellstrom subgp with DM 2009 Multi20

Median 4 y (2 y)


(388) 343

(343) CKD 5HD 100 (100) nd nd nd nd 135 (13%)

[136 (15%)] RR 0.88

(0.73, 1.06) 77

nd Fair

Composite cardiac endpoint of cardiac death or nonfatal MI

AURORA Holdaas subgp with DM 201121 Multi

3 y (2 y)


(388 343

(343) CKD 5HD 100% 4.49

(4.35) mmol

/L

2.51 (2.43) mmol

/L

1.11 (1.08) mmol

/L

1.90 (1.85) mmol

/L

85 (22%) [104 (30%)]

HR 0.68 (0.51, 0.90) 0.008 Good

Cardiac death, nonfatal MA, fatal or nonfatal stroke

Risk reduction 16.2% for

DM

HR 0.838 (0.654, 1.074)

NS Good

Mortality Death from all causes


4 y (2 y)

Atorvastatin Placebo

619 (619)

636 (636)

CKD 5HD 100 (100)

218 (220)

125 (127)

36 (36)

261 (267)

297 (48) [320 (50%)]

RR 0.93 (0.79, 1.08) NS Good

Death from causes other than CV or cerebrovascular disease

149 (24%) [158 (25%)]

RR 0.95 (0.76, 1.18) NS Good

All-cause mortality for CRP quartile 1 (≤2.3 mg/L)

4D Krane 2008 Germany19

4 y (2 y)

316 (316)

nd

126

nd nd

64 [55]

HR 1.07 (0.74, 1.55) NS Fair

All-cause mortality for CRP quartile 2 (>2.3-≤5 mg/L)

310 (310) 128 67

[77] HR 0.73

(0.53, 1.02) NS

(0.067) Fair

All-cause mortality for CRP quartile 3 (>5-≤12.4 mg/L)

312 (312) 126 63

[94] HR 0.79

(0.57, 1.11) NS Fair

77 Calculated by ERT

27

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




All-cause mortality for CRP quartile 4 (>12.4 mg/L)

311 (311) 122 101

[91] HR 1.02

(0.77, 1.37) NS Fair

All-cause mortality in 2nd and 3rd CRP quartiles combined

622 (622) nd 130

[171] HR 0.78

(0.62, 0.99) 0.038 Fair

Death from any cause


3 y (2 y)


(388) 343

(343) CKD 5HD 100% 4.49

(4.35) mmol

/L

2.51 (2.43) mmol

/L

1.11 (1.08) mmol

/L

1.90 (1.85) mmol

/L

219 (56%) [213 (62%)]

HR 0.86 (0.71, 1.04) NS Good

CV Mortality

Cardiac mortality

4D Wanner 2005 Germany 18


(619) 636

(636) CKD 5HD 100 (100)

218 (220)

125 (127)

36 (36)

261 (267)

121 (20%) [149 (23%)]

RR 0.81 (0.64, 1.03)

NS (0.08) Good

Deaths attributable to cardiac disease


3 y (2 y)


(388) 343

(343) CKD 5HD 100% 4.49

(4.35) mmol

/L

2.51 (2.43) mmol

/L

1.11 (1.08) mmol

/L

1.90 (1.85) mmol

/L

35% [47%] -- nd Good

Fatal cardiac events

64% [71%] -- nd Good

CV events

Nonfatal MI



(619) 636

(636) CKD 5HD 100 (100)

218 (220)

125 (127)

36 (36)

261 (267)

70 (11%) [79 (12%)]

RR 0.88 (0.64, 1.21) NS Good

Fatal stroke 27 (4%) [13 (2%)]

RR 2.03 (1.05, 3.93) 0.04 Good

Nonfatal stroke 33 (5%) [32 (5%)]

RR 1.04 (0.64, 1.69) NS Good

All cardiac events combined

205 (33%) [246 (39%)]

RR 0.82 (0.68, 0.99) 0.03 Good

All cerebrovascular events combined

79 (13%) [70 (11%)]

RR 1.12 (0.81, 1.55) NS Good

Stroke 59 (10%) [44 (7%)]

RR 1.33 (0.90, 1.97) NS Good

28

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




Hemorrhagic stroke

AURORA Fellstrom subgp with DM 2009 Multi20

Median 4 y

(2 y) Rosuvastati

n Placebo 388 (388)

343 (343) CKD 5HD 100

(100) nd nd nd nd 12 (4%) [2 (1%)]

RR 5.30 (1.20-

23.53)78 0.07 Fair

Stroke AURORA Holdaas subgp with DM 201121 Multi

3 y (2 y)


(388 343

(343) CKD 5HD 100% 4.49

(4.35) mmol

/L

2.51 (2.43) mmol

/L

1.11 (1.08) mmol

/L

1.90 (1.85) mmol

/L

38 (10%) [20 (6%)]

HR 1.65 (0.96, 2.83)

NS (0.07) Good

Fatal stroke 18 (5%) [11 (3%)]

HR 1.41 (0.67, 2.99) NS Good

Hemorrhagic strokes

12 (3%) [2 (0.6%)]

HR 5.21 (1.17, 23.27)

0.031 Good

Dialysis without DM Composite outcome Time to CV event defined as a nonfatal MI, nonfatal stroke, or death from CV cause (primary) AURORA

Fellstrom 2009 Multi20

Median 4 y

(2 y) Rosuvastati

n Placebo 1389 (1391)

1384 (1385) CKD 5HD 21

(18) 176

(174) 100 (99)

45 (45)

157 (154)

9.2/100 pt-y [9.5/100 pt-

y] -- -- Good

CV event defined as a nonfatal MI, nonfatal stroke, or death from CV cause (primary)

396 (29%) [408 (29%)]

HR 0.96 (0.84, 1.11) NS Good

Mortality

Time to death from any cause AURORA


Median 4 y

(2 y) Rosuvastati

n Placebo 1389 (1391)

1384 (1385) CKD 5HD 21

(18) 176

(174) 100 (99)

45 (45)

157 (154)

13.5/100 pt-y

[14.0/100 pt-y]

-- -- Good

Death from any cause

636 (46%) [660 (48%)]

HR 0.96 (0.86, 1.07) NS Good


29

Outcome Author,

Year Country

Ref #

Duration Outcome




SCr DM (%)




Time to death from non-CV cause

5.5/100 pt-y [6.0/100 pt-

y] -- -- Good

Death from non-CV cause

248 (18%) [268 (19%)]

HR 0.92 (0.77, 1.09) NS Good

CV mortality

Time to CV mortality AURORA


Median 4 y

(2 y) Rosuvastati

n Placebo 1389 (1391)

1384 (1385) CKD 5HD 21

(18) 176

(174) 100 (99)

45 (45)

157 (154)

7.2/100 pt-y [7.3/100 pt-

y] -- -- Good

CV mortality 324 (23%) [324 (23%)]

HR 1.00 (0.85, 1.16) NS Good

CV events

Time to nonfatal MI

AURORA Fellstrom 2009 Multi20

Median 4 y

(2 y) Rosuvastati

n Placebo 1389 (1391)

1384 (1385) CKD 5HD 21

(18) 176

(174) 100 (99)

45 (45)

157 (154)

2.1/100 pt-y [2.5/100 pt-

y] -- -- Good

Nonfatal MI 91 (7%) [107 (8%)]

HR 0.84 (0.64, 1.11) NS Good

Time to nonfatal stroke

1.2/100 pt-y [1.1/100 pt-

y] -- -- Good

Nonfatal stroke 53 (4%) [45 (3%)]

HR 1.17 (0.79, 1.75) NS Good

30

Supplemental Table 12: Summary table of RCTs of statins vs. placebo in dialysis patients with and without DM [continuous outcomes]

Outcome (Units)


Ref #

Duration Outcome



value Quality Intervention Control Intervention Control GFR or SCr DM

(%) Baseline


Final Intervention

(Control)

∆ Intervention

(Control) Net ∆

(95% CI)

Dialysis with DM Lipid levels

∆LDL, mg/dL 4D Wanner 2005 Germany18

4 wk (2 y) Atorvastatin Placebo

619 (619)

636 (636) CKD 5HD 100

(100) 125

(127)

72 (120)

-53 (-7) -46 nd Fair

5 y (2 y)

44 (619)

37 (636)

7079 (92)

-55 (-35) -20 nd Fair

∆LDL, mmo/L AURORA Holdaas subgp with DM 201121 Multi

3 mo (2 y) Rosuvastatin Placebo 388

(388 343

(343) CKD 5HD 100

2.51 (2.43)

1.41 (2.43)

-1.1 (0) -1.1 nd Good


4.49 (4.35)

3.29 (nd)

-1.2 (nd) nd nd Fair

Dialysis without DM Lipid levels

∆LDL, mg/dL

AURORA Fellstrom 2009 Multi20

Median 4y

(2 y) Rosuvastatin Placebo 1389

(1391) 1384

(1385) CKD 5HD 21 (18)

100 (99)

58 (97.1)

-42 (-1.9) -43.9 <0.001 Good

∆Total cholesterol, mg/dL

176 (174)

129 (173)

-47 (-1) -48 <0.001 Good


157 (154)

131 (155.8)

-26 (+1.8) -24.2 <0.001 Good

∆HDL, mg/dL 45 (45)

46.2 (44.6)

+1.2 (+0.4) 1.6 0.045 Good

∆LDL, mg/dL

147 (145)

98 (135)80

-48.5 (-9.5) -39 nd Good81


165 (164)

129 (165)82

-35.5 (+1) -36.5 nd Good83

79 Estimated from figure 80 Estimated from graph 81 Study is graded “Good” however consider downgrading in EP due to the fact that “there was no significant interaction of baseline eGFR and treatment group”. 82 Estimated from graph 83 Study is graded “Good” however consider downgrading in EP due to the fact that “there was no significant interaction of baseline eGFR and treatment group”.

31

Supplemental Table 13: Evidence profile of RCTs examining the effect of statins vs. placebo in dialysis patients with and without DM


and study design

Total N (treatment)



across studies




Summary of findings

Quality of evidence for outcome

Qualitative and quantitative description of effect

Importance of outcome

Composite outcomes

DM 2 RCTs (High)

1986 (1007)

No limitations (0)


(0) Direct

(0) None

(0) High No difference in patients with DM Critical

NonDM

1 RCT (High

2773 (1389)

No limitations (0) NA Direct

(0) Sparse

(-1) Moderate No difference in patients without DM

Mortality DM 2 RCTs

(High) 1986

(1007) No limitations

(0) No important

inconsistencies (0)

Direct (0)

Sparse (-1) Moderate No difference in patients with DM

Critical NonDM

1 RCT (High

2773 (1389)


(0) Sparse


CV mortality DM 2 RCTs

(High) 1986

(1007) No limitations

(0) No important

inconsistencies (0)

Direct (0)

Sparse (-1) Moderate Possible benefit from statins in patients with

DM Critical NonDM

1 RCT (High

2773 (1389)


(0) Sparse


CV events DM 2 RCTs

(High) 1790 (905)

No limitations (0)


(0) Direct

(0) None

(0) Moderate Possible benefit from statins for patients with DM Critical

NonDM

1 RCT (High

2773 (1389)


(0) Sparse


ESRD DM 0 RCTs -- -- -- -- -- --

-- Critical NonDM 0 RCTs -- -- -- -- -- --


DM 0 RCTs -- -- -- -- -- -- -- High Non

DM 0 RCTs -- -- -- -- -- --


DM 2 RCTs (High)

1986 (1007)

Some limitations (-1)


(0)


(-1) None

(0) Low Benefit from statins in patients with DM

Moderate NonDM

1 RCT (High

2773 (1389)

No limitations (0) NA


(-1) Sparse

(-1) Low Benefit from statins in patients without DM

Adverse events 3 RCTs 4759 (2396) No difference in AEs for patients with and

without DM Moderate

Total 3 RCTs 4759 (2396)

Balance of potential benefits and harms: No difference

Quality of overall evidence: Moderate

32

Supplemental Table 14: Summary table of RCT examining statin vs. placebo in patients with ADPKD [continuous outcomes]


Country Ref #

Duration Outcome




(%) Baseline


Final Intervention

(Control)

∆ Intervention

(Control) Net ∆

(95% CI)

Lipid levels ∆Total cholesterol, mmol/L

Fasset 2010 Australia22

2 y (2 y)

Pravastatin 20 mg/day Control 29

(31) 20

(29)

GFR 58.5 (49.9)

mL/min/1.73 m2

nd

5.22 (4.91)

4.91 (4.95)

-0.35 (0.04) -0.39 nd Fair

∆LDL, mmol/L 3.52 (3.08)

2.98 (2.92)

-0.38 (-0.16) -0.22 nd Fair

∆HDL, mmol/L 1.08 (1.38)

1.29 (1.50)

0.10 (0.11) -0.01 nd Fair

∆Triglycerides, mmol/L

1.65 (1.19)

1.47 (1.30)

-0.29 (0.11) -0.4 nd Fair

33

Supplemental Table 15: Summary table of RCT examining simvastatin/ezetimibe combination vs. simvastatin/placebo in CKD patients without DM [categorical outcomes]

Outcome Author,

Year Country

Ref #

Duration Outcome




(%) TC LDL HDL Tg Events

No. (%) Intervention

[Control]


Mortality

Death UK-HARP II Landray 2006 UK23

6 mo (6 mo)

Simvastatin 20 mg/d

Ezetimibe 10mg/d

Simvastatin 20 mg/d

102 (102)

101 (101)

GFR 26.1 (29.7)

mL/min/1.73 m2 12

(10) 198

(195) 121

(117) 40

(40) 167

(188) 3 (2%)

[0 (0%)] nd nd Good

Kidney function

ESRD UK-HARP II Landray 2006 UK23

6 mo (6 mo)

Simvastatin 20 mg/d

Ezetimibe 10mg/d

Simvastatin 20 mg/d

102 (102)

101 (101)

GFR 26.1 (29.7)

mL/min/1.73 m2 12

(10) 198

(195) 121

(117) 40

(40) 167

(188) 14 (14%) [14 (14%)]

RR 0.99 (0.50, 1.97)84

NS Good


34

Supplemental Table 16: Summary table of RCT examining simvastatin/ezetimibe combination vs. simvastatin/placebo in CKD patients without DM [continuous outcomes]

Outcome Author,

Year Country

Ref #

Duration Outcome


Description No. Analyzed (Enrolled) Baseline Results (Lipids) P value Quality



(Control)

Final Intervention

(Control)

∆ Intervention

(Control) Net ∆

(95% CI)

Lipid levels ∆Total cholesterol, mg/dL

UK-HARP II Landray 2006 UK23

6 mo (6 mo)

Simvastatin 20 mg/d

Ezetimibe 10mg/d

Simvastatin 20 mg/d

102 (102)

101 (101)

GFR 26.1 (29.7)

mL/min/1.73 m2 12

(10)

198 (195)

139 (158)

-59 (-37) -2285 <0.001 Good

∆LDL, mg/dL 121 (117)

72 (86)

-49 (-31) -1886 <0.001 Good

∆HDL, mg/dL

40 (40)

40 (39)

0 (-1) 187 NS Good


167 (188)

135 (171)

-32 (-17) -1688 NS Good

85 Mean absolute difference adjusted for baseline differences 86 Mean absolute difference adjusted for baseline differences 87 Mean absolute difference adjusted for baseline differences 88 Mean absolute difference adjusted for baseline differences

35

Supplemental Table 17: Summary table of RCT of statin + ezetimibe vs. placebo in CKD patients [categorical outcomes]

Outcome Author,

Year Country

Ref #

Duration Outcome



P value Quality Intervention Control Intervention Control

GFR or SCr

(units) DM (%)



RR/OR/HR (95% CI)

(mmol/L)

Composite outcomes

ESRD or death

SHARP 2011 Multi24

5 y (4 y)

Simvastatin 20 mg/d +

ezetimibe 10 mg/d

Placebo 4650 (4650)

4620 (4620)

GFR 27 (27)

mL/min/ 1.73 m2

23 (23)

4.88 (4.90)

2.77 (2.78)

1.12 (1.11)

2.31 (2.34)

1477 (47%) [1513 (48%)]

RR 0.97 (0.90, 1.04) NS Good

Mortality All-cause mortality

SHARP 2011 Multi24

5 y (4 y)


ezetimibe 10 mg/d

Placebo 4650 (4650)

4620 (4620)

GFR 27 (27)

mL/min/ 1.73 m2

23 (23)

4.88 (4.90)

2.77 (2.78)

1.12 (1.11)

2.31 (2.34)

1142 (25%) [1115 (24%)]

RR 1.02 (0.94, 1.11) NS Good

Death from any cancer

150 (3%) [128 (3%)]

RR 1.17 (0.92, 1.48) nd Good

Death from renal causes

164 (4%) [173 (4%)]

RR 0.95 (0.76, 1.17) nd Good

Death from respiratory causes

124 (3%) [100 (2%)]

RR 1.24 (0.95,1.61) nd Good

Death from GI causes

72 (2%) [70 (2%)]

RR 1.03 (0.74, 1.42) nd Good

Death from other medical causes

124 (3%) [119 (3%)]

RR 1.04 (0.81, 1.34) nd Good

Death from trauma or fracture

34 (1%) [22 (1%)]

RR 1.53 (0.91, 2.59) nd Good

Any nonvascular death

668 (14%) [612 (13%)]

RR 1.09 (0.98, 1.21) NS Good

Sudden death

50 (1%) [55 (1%)]

RR 0.91 (0.62, 1.33) nd Good

Death for reasons unclear

63 (1%) [60 (1%)]

RR 1.05 (0.74, 1.49) nd Good

Death from unknown causes

113 (2%) [115 (3%)]

RR 0.98 (0.76, 1.27) NS Good

CV mortality

CHD death SHARP 2011 Multi24

5 y (4 y)

Simvastatin 20 mg/d + Placebo 4650

(4650) 4620

(4620) GFR 27

(27) 23

(23) 4.88

(4.90) 2.77

(2.78) 1.12

(1.11) 2.31

(2.34) 91 (2%) [90 (2%)]

RR 1.01 (0.75, 1.35) NS Good

36

Cardiac death other than CHD

ezetimibe 10 mg/d

mL/min/1.73 m2 162 (4%)

[182 (4%)] RR 0.89

(0.72, 1.09) nd Good

All cardiac deaths

253 (5%) [272 (6%)]

RR 0.93 (0.78, 1.10) NS Good

Death from ischemic stroke

30 (1%) [41 (1%)]

RR 0.73 (0.46, 1.16) nd Good

Death from haemorrhagic stroke

27 (1%) [23 (1%)]

RR 1.16 (0.67, 2.03) nd Good

Death from unspecified stroke

11 (0.2%) [14 (0.3%)]

RR 0.78 (0.36, 1.71) nd Good

Death from any type of stroke

68 (2%) [78 (2%)]

RR 0.87 (0.63, 1.20) NS Good

Any other vascular death

40 (1%) [38 (1%)]

RR 1.05 (0.67, 1.64) NS Good

Any vascular death (total)

361 (8%) [388 (8%)]

RR 0.93 (0.80, 1.07) NS Good

CV event Any major coronary event

SHARP 2011 Multi24

5 y (4 y)


ezetimibe 10 mg/d

Placebo 4650 (4650)

4620 (4620)

GFR 27 (27)

mL/min/1.73 m2

23 (23)

4.88 (4.90)

2.77 (2.78)

1.12 (1.11)

2.31 (2.34)

213 (5%) [230 (5%)]

RR 0.92 (0.76, 1.11) NS Good

Non-fatal MI 134 (3%) [159 (3%)]

RR 0.84 (0.66, 1.05) NS Good

Any non-haemorrhagic stroke

131 (3%) [174 (4%)]

RR 0.75 (0.60, 0.94) 0.01 Good

Ischemic stroke

114 (3%) [157 (3%)]

RR 0.72 (0.57, 0.92) 0.0073 Good

Unknown stroke

18 (0.4%) [19 (0.4%)]

RR 0.94 (0.49, 1.79) NS Good

Any stroke 171 (4%) [210 (5%)]

RR 0.81 (0.66, 0.99) 0.04 Good

Haemorrhagic stroke

45 (1%) [37 (1%)]

RR 1.21 (0.78, 1.86) NS Good

Any revascularization procedure

284 (6%) [352 (8%)]

RR 0.79 (0.68, 0.93) 0.0036 Good


149 (3%) [203 (4%)]

RR 0.73 (0.59, 0.90) 0.0027 Good

37

Non-coronary revascularization

154 (3%) [169 (4%)]

RR 0.90 (0.73, 1.12) NS Good

First major atherosclerotic events89

596 (11%) [619 (13%)]

RR 0.83 (0.74, 0.94) 0.0021 Good

Major vascular events90

701 (15%) [814 (18%)]

RR 0.85 (0.77, 0.94) 0.0012 Good

PCI 106 (2%) [148 (3%)]

RR 0.71 (0.56, 0.91) 0.0063 Good

CABG 50 (1%) [66 (1%)]

RR 0.75 (0.52, 1.09) 0.13 Good

Major atherosclerotic events in CKD 1-2

44 (44)

44 (44)

GFR ≥ 60

mL/min/1.73 m2

nd nd nd nd nd

3 (7%) [3 (7%)]

RR 0.84 (0.17, 4.18) nd Good

Major atherosclerotic events in CKD 3

1100 (1100)

1055 (1055)

GFR ≥30-<60 mL/min/1.73 m2

87 (8%) [110 (10%)]

RR 0.75 (0.57, 1.00) nd Good


1246 (1246)

1319 (1319)

GFR ≥15-<30 mL/min/1.73 m2

127 (10%) [168 (13%)]

RR 0.78 (0.62, 0.98) nd Good


614 (614)

607 (607)

GFR <15

mL/min/1.73 m2

67 (11%) [81 (13%)]

RR 0.82 (0.59, 1.13) nd Good

Major atherosclerotic events in CKD 5HD

1275 (1275)

1252 (1252)

nd

194 (15%) [199 (16%)]

RR 0.95 (0.78, 1.15) nd Good

Major atherosclerotic events in CKD 5PD

258 (258)

238 (238)

36 (14%) [47 (20%)]

RR 0.70 (0.46, 1.08) nd Good

Major atherosclerotic events in CKD 5D

1533 (1533)

1490 (1490)

230 (15%) [246 (17%)]

RR 0.90 (0.75, 1.08) nd Good

89 Non-fatal MI or coronary death, nonhaemorrhagic stroke, or arterial revascularization 90 Major atherosclerotic events plus non-coronary cardiac deaths and haemorrhagic strokes)

38

Kidney function ESRD defined as dialysis or transplantation

SHARP 2011 Multi24

5 y (4 y)


ezetimibe 10 mg/d

Placebo 4650 (4650)

4620 (4620)

GFR 27 (27)

mL/min/1.73 m2

23 (23)

4.88 (4.90)

2.77 (2.78)

1.12 (1.11)

2.31 (2.34)

1057 (34%) [1084 (35%)]

RR 0.97 (0.89, 1.05) NS Good

ESRD or doubling of SCr

1190 (38%) [1257 (40%)]

RR 0.93 (0.86, 1.01)

NS (0.09) Good

39

Supplemental Table 18: Summary table of RCT examining the effect of dose of atorvastatin in CKD patients with DM [categorical outcomes]

Outcome Author,

Year Country

Ref #

Duration Outcome measure-

ment (Treatment)

Description No. Analyzed (Enrolled) Baseline Results*

P value91 Quality

Intervention Control Intervention Control eGFR DM (%)



RR/HR92 (95% CI) mg/dL

Mortality

All-cause mortality

TNT Shepherd 2008 Multi25 Median

5 y (5 y)

80-mg Atorvastatin

10-mg Atorvastatin

273 (273)

273 (273)

51.5 (50.7)

mL/min/ 1.73 m2

100 (100)

176.1 (178.0)

95.5 (97.0)

44.9 (45.2)

181.6 (180.2)

33 (12%) [32 (12%)]

RR 1.03 (0.65, 1.63)

NS Good

TNT Shepherd 2008 Multi26

1602 (1602)

1505 (1505)

53.0 (52.8)

mL/min/ 1.73 m2

17 (18)

175.9 (175.9)

96.3 (96.5)

48.0 (47.6)

159.2 (159.8)

112 (7%) [113 (8%)]

HR 0.95 (0.70, 1.2)93

NS Good

CV events Major CV event (primary)94


Median 5 y (5 y)

80-mg Atorvastatin

10-mg Atorvastatin

273 (273)

273 (273)

51.5 (50.7)

mL/min/ 1.73 m2

100 (100)

176.1 (178.0)

95.5 (97.0)

44.9 (45.2)

181.6 (180.2)

38 [14%) [57 (21%)]

HR 0.65 (0.43, 0.98)

0.04 Good

Any CV event

120 (44%) [140 (51%)]

RR 0.86 (0.72, 1.02)

NS (0.08) Good

Major coronary event95

28 (10%) [43 (16%)]

RR 0.65 (0.42, 1.02)

NS (0.06) Good

Any coronary event

80 (29%) [97 (36%)]

RR 0.82 (0.65, 1.05)

NS Good

Cerebrovascular event

24 (9%) [36 (13%)]

RR 0.67 (0.41, 1.09)

NS Good

Stroke 13 (5%) [20 (7%)]

RR 0.65 (0.33, 1.28)

NS Good

91 Calculated by ERT for all outcome other than primary outcome of major CV event 92 Calculated by ERT for all outcome other than primary outcome of major CV event 93 Estimated from figure 94 Death from CHD, nonfatal non-procedure-related MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke. 95 Death from CHD, nonfatal non-procedure-related MI, or resuscitation after cardiac arrest.

40

Outcome Author,

Year Country

Ref #

Duration Outcome measure-

ment (Treatment)

Description No. Analyzed (Enrolled) Baseline Results*

P value91 Quality

Intervention Control Intervention Control eGFR DM (%)



RR/HR92 (95% CI) mg/dL

CHF with hospitalization

25 (9%) [34 (13%)]

RR 0.74 (0.45, 1.20)

NS Good

Peripheral artery disease

35 (13%) [30 (11%)]

RR 1.17 (0.74, 1.84)

NS Good

Major CV event (primary)


1602 (1602)

1505 (1505)

53.0 (52.8)

mL/min/ 1.73 m2

17 (18)

175.9 (175.9)

96.3 (96.5)

48.0 (47.6)

159.2 (159.8)

149 (9%) [202 (13%)]

HR 0.68 (0.55, 0.84)

0.0003 Good

Any CV event

489 (31%) [574 (38%)]

HR 0.76 (0.67, 0.86)

nd Good

Major coronary event

110 (7%) [157 (10%)

HR 0.65 (0.51, 0.83)

nd Good

Any coronary event

356 (22%) [431 (29%)]

HR 0.75 (0.65, 0.86)

nd Good

Cerebrovascular event

74 (5%) [104 (7%)]

HR 0.66 (0.49, 0.89)

nd Good

CHF with hospitalization

49 (3%) [84 (6%)]

HR 0.54 (0.38, 0.77)

nd Good

Peripheral artery disease

121 (8%) [112 (7%)]

HR 1.0 (0.8, 1.4)96

nd Good

96 Estimated from figure

41

Supplemental Table 19: Drug interactions Simvastatin Lovastatin Atorvastatin Fluvastatin Pravastatin Rosuvastatin Pitavastatin Reference # Inhibitors (increase statin AUC)

Potent CYP3A4 inhibitors (eg, itraconazole)

5- to 20-fold increase



<1.5-fold <1.5-fold <1.5-fold Unchanged 27-32

Moderate CYP3A4 inhibitors (eg, clarithromycin and diltiazem)




Unchanged <2-fold Unchanged Unchanged 33, 34

Cyclosporine (an OATP1B1 and CYP3A$ inhibitor)

6- to 10-fold incrase






5-fold increase 32, 35-37

Gemfibrozil (a CYP2C8 and OATP1B1 inhibitor)



<1.5-fold increase

unchanged 2-fold increase

2-fold increase ≤1.5-fold increase

38-44

Inducers (decrease statin AUC)

Potent inducers of CYP3A4 (eg, rifampicin and carbamazepine)

70 to 95% decrease

70 to 95% decrease

60 to 90% decrease

50% decrease

30% decrease

Unchanged Unknown 39

42

Supplemental Table 20: From Vaquero et al. 201045

43

Supplemental Table 21: Patients on statin + fibrate therapy reporting any adverse event Study Year

Country Ref #

Population Duration Outcome


Description No analyzed (Enrolled) Baseline

GFR or SCr % with DM Results

P value Intervention Control Interventi

on Control Definition No. (%)


RR97 (95% CI)

Wiklund 1993 Sweden & Finland46

Adults with hypercholest

erolemia 12 wk

(12 wk) Pravastatin + gemfibrozil

Placebo

75 (75)

73 (73)

nd nd Any AE

31 (41%) [21 (29%)]

1.44 (0.92, 2.25) nd

Pravastatin 70 (70) 31 (41%) [16 (23%)]

1.81 (1.09, 3.00) nd

Gemfibrozil 72 (72) 31 (41%) [25 (35%)]

1.19 (0.79, 1.80) nd

Roth 2010 US47


erolemia and

hypertriglyceridemia

12 wk (8 wk)

5 mg rosuvastatin + fenofibric acid

Simvastatin98

118 (118)

119 (119) nd

22 (16)

Treatment emergent

AE

53 (45%) [58 (49%)]

0.92 (0.70, 1.21) nd


119 (119) 19 (16)

45 (38%) [58 (49%)]

0.78 (0.58, 1.04) nd


118 (118) 23 (16)

71 (60%) [58 (49%)]

1.23 (0.98, 1.56) nd

Jones 2010 US & Canada48 [Subgroup analysis of 3 RCTs]

Adults with mixed

dyslipidemia 2 y

(2 y)

Fenofibric acid + low-

dose rosuvastatin, simvastatin,

or atorvastatin

Fenofibric acid

106 (106)

105 (105)

nd 100 (100)

Any treatment-emergent

AE

82 (77%) [70 (67%)]

1.16 (0.98, 1.38) nd

Low-dose statin only 105 (105) 82 (77%)

[57 (54%)] 1.43

(1.16, 1.75) nd

Moderate-dose statin

only 107 (107) 82 (77%)

[72 (67%)] 1.15

(0.97, 1.36) nd

Fenofibric acid +

moderate-dose

rosuvastatin, simvastatin,

or atorvastatin

Fenofibric acid

110 (110)

105 (105) 83 (76%) [70 (67%)]

1.13 (0.95, 1.34) nd


[57 (54%)] 1.39

(1.13, 1.71) nd

97 Calculated by ERT 98 FDA issued a Drug Safety Communication on June 8, 2011, about limiting use of the highest approved dose, 80 mg, because of increased risk of muscle damage. (See http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm).

44

Study Year Country

Ref # Population

Duration Outcome







RR97 (95% CI)

Moderate dose statin

only 107 (107) 83 (76%)

[72 (67%)] 1.12

(0.95, 1.33) nd

Jones 2010 US49

Adults with mixed

dyslipidemia 16 wk

(12 wk)

Fenofibric acid +

atorvastatin and ezetimibe

Placebo + atorvastatin

and ezetimibe

272 (272) 270 (271) nd 20 (23) Any AE 138 (51%)

[137 (51%)] 1.00

(0.85, 1.18) nd

Farnier 2010 EU50

Adults with mixed

dyslipidemia 12 wk

(12 wk) Fenofibrate + pravastatin Pravastatin 123 (123) 125 (125) SCr 84.2 (8.5)

µmol/L 26

(29) Any AE 45 (37%) [40 (32%)]

1.14 (0.81, 1.62) nd

Farnier 2007 Multi51

Adults with mixed

hyperlipidemia

12 wk (12 wk)

Ezetimibe + simvastatin

and fenofibrate


183 (183)

184 (184) Median SCr

1.1 (1.1) mg/dL

12 (6)

One or more AEs

72 (39%) [65 (35%)]

1.11 (0.85,1.45) nd

Fenofibrate 184 (184) Median SCr

1.1 (1.0) mg/dL

12 (9)

72 (39%) [87 (47%)]

0.83 (0.66, 1.05) nd

Placebo 60 (60) Median SCr

1.1 (1.0) mg/dL

12 (10)

72 (39%) [18 (30%)]

5.97 (3.69, 9.66) nd

Davidson 2009 US52

Adults with dyslipidemia

12 wk (12 wk)

Atorvastatin + fenofibrate Atorvastatin 73 (73) 74 (74) SCr 1.0 (0.9)

mg/dL nd Treatment-emergent

AE 43 (59%) [49 (66%)]

0.89 (0.69, 1.14) nd

45

Study Year Country

Ref # Population

Duration Outcome







RR97 (95% CI)

Fenofibrate 73 (73) SCr 1.0 (1.0) mg/dL

43 (59%) [48 (66%)]

0.90 (0.70, 1.15) nd

46

Supplemental Table 22: Patients receiving statin + fibrate therapy reporting other individual adverse events Study Year

Country Ref #



Description No analyzed (Enrolled) Baseline GFR or

SCr % with

DM

Results P value

Intervention Control Intervention Control Definition No. (%) Intervention [Control]

RR (95% CI)99



erolemia 12 wk

(12 wk)

Pravastatin + gemfibrozil

Placebo

75 (75)

73 (73)

nd nd

Abdominal pain

5 (7%) [0 (0%)] -- nd

Pravastatin 70 (70) 5 (7%) [0 (0%)] -- nd

Gemfibrozil 72 (72) 5 (7%) [7 (10%)]

0.69 (0.23, 2.06) nd


Placebo

75 (75)

73 (73)

Diarrhea

4 (5%) [2 (3%)]

1.95 (0.37, 10.31) nd

Pravastatin 70 (70) 4 (5%) [0 (0%)] -- nd

Gemfibrozil 72 (72) 4 (5%) [2 (3%)]

1.92 (0.36, 10.16) nd


Placebo

75 (75)

73 (73)

Dizziness

2 (3%) [0 (0%)] -- nd

Pravastatin 70 (70) 2 (3%) [1 (1%)]

1.87 (0.17, 20.13) nd

Gemfibrozil 72 (72) 2 (3%) [2 (3%)]

0.96 (0.14, 6.63) nd


Placebo

75 (75)

73 (73)

Dyspepsia/heartburn

0 (0%) [0 (0%)] -- nd

Pravastatin 70 (70) 0 (0%) [1 (1%)] -- nd

Gemfibrozil 72 (72) 0 (0%) [3 (4%)] -- nd


Placebo

75 (75)

73 (73)

Epigastric pain

2 (3%) [2 (3%)]

0.97 (0.14, 6.73) nd

Pravastatin 70 (70) 2 (3%) [1 (1%)]

1.87 (0.17, 20.13) nd

Gemfibrozil 72 (72) 2 (3%) [0 (0%)] -- nd


Placebo

75 (75)

73 (73)

Fatigue

0 (0%) [1 (1%)] -- nd

Pravastatin 70 (70) 0 (0%) [1 (1%)] -- nd

Gemfibrozil 72 (72) 0 (0%) [2 (3%)] -- nd

99 All RRs and CIs were calculated by ERT.

47

Study Year Country

Ref # Population

Duration Outcome



SCr % with

DM

Results P value


RR (95% CI)99


Placebo

75 (75)

73 (73)

Fever

1 (1%) [3 (3%)]

0.32 (0.03, 3.05) nd

Pravastatin 70 (70) 1 (1%) [1 (1%)]

0.93 (0.06, 14.64) nd

Gemfibrozil 72 (72) 1 (1%) [0 (0%)] -- nd


Placebo

75 (75)

73 (73)

Gastritis

1 (1%) [0 (0%)] -- nd

Pravastatin 70 (70) 1 (1%) [0 (0%)] -- nd

Gemfibrozil 72 (72) 1 (1%) [6 (8%)]

0.16 (0.02, 1.30) nd


Placebo

75 (75)

73 (73)

Headache

1 (1%) [3 (4%)]

0.32 (0.03, 3.05) nd

Pravastatin 70 (70) 1 (1%) [0 (0%)] -- nd

Gemfibrozil 72 (72) 1 (1%) [0 (0%)] -- nd


Placebo

75 (75)

73 (73)

Malaise

2 (3%) [0 (0%)] -- nd

Pravastatin 70 (70) 2 (3%) [0 (0%)] -- nd

Gemfibrozil 72 (72) 2 (3%) [2 (3%)]

0.96 (0.14, 6.63) nd


Placebo

75 (75)

73 (73)

Musculoskeletal pain

7 (9%) [3 (4%)]

2.27 (0.61, 8.45) nd

Pravastatin 70 (70) 7 (9%) [1 (1%)]

6.53 (0.82, 51.77) nd

Gemfibrozil 72 (72) 7 (9%) [3 (4%)]

2.24 (0.60, 8.33) nd


Placebo

75 (75)

73 (73) Upper

respiratory infection

6 (8%) [5 (7%)]

1.17 (0.37, 3.66) nd

Pravastatin 70 (70) 6 (8%) [2 (3%)]

2.80 (0.58, 13.42) nd

Gemfibrozil 72 (72) 6 (8%) [3 (4%)]

1.92 (0.50, 7.39) nd

Farnier 2010 EU50

Adults with mixed

dyslipidemia 12 wk

(12 wk) Fenofibrate

+ pravastatin Pravastatin 123 (123) 125 (125) SCr 84.2 (85.5) µmol/L

26 (29)

GI AEs 5 (4%) [4 (3%)]

1.27 (0.35, 4.62) nd

Musculoskeletal AE

5 (4%) [4 (3%)]

1.27 (0.35, 4.62) nd

48

Study Year Country

Ref # Population

Duration Outcome



SCr % with

DM

Results P value


RR (95% CI)99

Myalgia 8 (7%) [8 (6%)]

1.02 (0.39, 2.62) nd

Nervous system AE

3 (2%) [2 (2%)

1.52 (0.26, 8.97) nd


Adults with mixed

hyperlipidemia

12 wk (12 wk)


and fenofibrate

Ezetimibe +, simvastatin

183 (183)

184 (184) Median SCr 1.1 (1.1)

mg/dL

12 (6)

Drug-related GI AE

7% [9%] -- nd

Fenofibrate 184 (184) Median SCr 1.1 (1.0)

mg/dL

12 (9)

7% [10%] -- nd

Placebo 60 (60) Median SCr 1.1 (1.0)

mg/dL

12 (6)

7% [7%] -- nd


and fenofibrate


183 (183)

184 (184) Median SCr 1.1 (1.1)

mg/dL

12 (6)

Myalgia

8 (4%) [7 (4%)]

1.15 (0.43, 3.10) nd


mg/dL

12 (9)

8 (4%) [6 (3%)]

1.34 (0.47, 3.79) nd


mg/dL

12 (6)

8 (4%) [0 (0%)] -- nd


and fenofibrate


183 (183)

184 (184) Median SCr 1.1 (1.1)

mg/dL

12 (6)

Rash

2% [1%] -- nd


mg/dL

12 (9)

2% [5%] -- nd

49

Study Year Country

Ref # Population

Duration Outcome



SCr % with

DM

Results P value


RR (95% CI)99


mg/dL

12 (6)

2% [7%] -- nd

Roth 2010 US47


erolemia and


12 wk (8 wk)

5 mg rosuvastatin + fenofibric

acid

Simvastatin

118 (118)

119 (119) nd

22 (16)

Muscle, hepatic, and renal AEs

3 (3%) [0 (0%)] -- nd

10mg rosuvastatin + fenofibric

acid 119 (119) 19

(16) 3 (3%)) [0 (0%)] -- nd


acid 118 (118) 23

(16) 5 (4%)

[0 (0%)] -- nd

Davidson 2009 US52


12 wk (12 wk)

Atorvastatin + fenofibrate

Atorvastatin

73 (73)

74 (74) SCr 1.0 (0.9)

mg/dL nd Muscle-

associated AEs except

myalgia

2 (3%) [5 (7%)]

0.41 (0.08, 2.02) nd

Fenofibrate 73 (73) SCr 1.0 (0.9)

mg/dL 2 (3%)

[3 (4%)] 0.67

(0.11, 3.87) nd


Atorvastatin

73 (73)

74 (74) SCr 1.0 (0.9)

mg/dL nd Myalgia

0 (0%) [2 (3%)] -- nd


mg/dL 0 (0%)

[2 (3%)] -- nd

Yang 2009 New Zealand53 [Post hoc analysis of 3 RCTs]

Adults with mixed

dyslipidemia Median 12 wk

(Median 12 wk)

Fenofibric acid+ low-

dose atorvastatin, rosuvastatin,

or simvastatin

Atorvastatin, rosuvastatin, or

simvastatin 1895 (1911) nd 19–26 Myalgia100

2–5% [3–5%] -- nd

Fenofibric acid 2–5% [3–7%] -- nd

100 Explicit report of “no myalgia”: Roth et al 201047. Roth EM, McKenney JM, Kelly MT, et al. Efficacy and safety of rosuvastatin and fenofibric acid combination therapy versus simvastatin monotherapy in patients with hypercholesterolemia and hypertriglyceridemia: a randomized, double-blind study. Am J Cardiovasc Drugs 2010; 10: 175-186.; Feher et al 199554. Feher MD, Foxton J, Banks D, et al. Long-term safety of statin-fibrate combination treatment in the management of hypercholesterolaemia in patients with coronary artery disease. Br Heart J 1995; 74: 14-17.

50

Study Year Country

Ref # Population

Duration Outcome



SCr % with

DM

Results P value


RR (95% CI)99


Adults with mixed

dyslipidemia 2 y

(2 y)

Fenofibric acid+ low


or atorvastatin

Fenofibric acid

106 (106)

105 (105)

nd 100 (100) Myalgia

2 (2%) [1 (1%)]

1.98 (0.18, 21.52) nd

Low dose statin 105 (105) 2 (2%) [6 (6%)]

0.33 (0.07, 1.60) nd

Moderate dose statin 107 (107) 2 (2%)

[2 (2%)] 1.01

(0.14, 7.04) nd

Fenofibric acid+

moderate dose


or atorvastatin

Fenofibric acid

110 (110)

105 (105) 3 (2%) [1 (1%)]

2.86 (0.30, 27.10) nd

Low dose statin 105 (105) 3 (2%) [6 (6%)]

0.95 (0.20, 4.62) nd


[2 (2%)] 1.46

(0.25, 8.56) nd

Jones 2010 US49

Adults with mixed

dyslipidemia 16 wk

(12 wk)

Fenofibric acid +

atorvastatin and

ezetimibe


and ezetimibe 272 (272) 270 (271) nd 20

(23) Myalgia 3% [4%] -- NS

Athyros 2001 Greece55

Patients with familial

combined hyperlipidemia, 48% with

and 52% without CAD

at entry

1 y

Simvastatin + gemfibrozil

Atorvastatin

135 (135)

134 (134) nd 100 (100)

Myalgia without CK elevation

1 (1%) [0 (0%)] -- nd

Pravastatin + gemfibrozil 136 (136) 1 (1%)

[0 (0%)] -- nd

51

Supplemental Table 23: Patients on statin + fibrate therapy reporting treatment related adverse events Study Year

Country Ref #




SCr % with DM

Results P value

Intervention Control Intervention Control Definition No. (%)


RR (95% CI)101


Adults with mixed


(Median 12 wk)

Fenofibric acid+ low- or

moderate-dose

atorvastatin, rosuvastatin,

or simvastatin

Atorvastatin, rosuvastatin,

or simvastatin

1895 (1911) nd 19–26 Treatment-related AEs

23–24% [16–24%] -- NS

Fenofibric acid

23–24% [13–33%] -- NS

Fenofibric acid +

atorvastatin Atorvastatin 20%

[6%] -- 0.003

Fenofibric acid +

rosuvastatin Rosuvastati

n 27% [17%] -- 0.006

Fenofibric acid +low-


or simvastatin

Low-dose atorvastatin, rosuvastatin,

or simvastatin

25% [14%] -- <0.05

Roth 2010 US47


erolemia and


12 wk (8 wk)


acid Simvastatin

118 (118)

119 (119) nd

22 (16)

Treatment-related AE

16 (14%) [20 (17%)]

0.81 (0.44, 1.48) nd


acid 119 (119) 19

(16) 17 (14%) [20 (17%)]

0.85 (0.47, 1.54) nd


52

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)101


acid 118 (118) 23

(16) 18 (15%) [20 (17%)]

0.91 (0.51, 1.63) nd

Jones 2010 US49

Adults with mixed

dyslipidemia 16 wk

(12 wk)

Fenofibric acid +

atorvastatin and

ezetimibe


and ezetimibe

272 (272) 270 (271) nd 20 (23)

Treatment-related AE

52 (19%) [45 (17%)]

1.15 (0.80, 1.65) nd

Farnier 2010 EU50

Adults with mixed

dyslipidemia 12 wk

(12 wk) Fenofibrate


26 (29)

Drug-related AE

13 (11%) [12 (10%)]

1.10 (0.52, 2.32) nd

Serious drug-related

AE 1 (1%) [0 (0%)] -- --


Adults with mixed

hyperlipidemia

12 wk (12 wk)


and fenofibrate


183 (183)

184 (184) Median SCr 1.1 (1.1)

mg/dL

12 (6)

Drug-related AEs

16 (9%) [13 (7%)]

1.24 (0.61, 2.50) nd


mg/dL

12 (9)

16 (9%) [23 (13%)]

0.70 (0.38, 1.28) nd


mg/dL

12 (10)

16 (9%) [4 (7%)] nd

Davidson 2009 US52


12 wk (12 wk)

Atorvastatin + fenofibrate Atorvastatin 73 (73) 74 (74)

SCr 1.0 (0.9)

mg/dL nd

Treatment emergent

AEs related 12 (16%) [17 (23%)]

0.72 (0.37, 1.39) nd

53

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)101


mg/dL

to the study drug 12 (16%)

[19 (26%)] 0.63

(0.33, 1.20) nd

54

Supplemental Table 24: Patients on statin + fibrate therapy discontinuing due to adverse events Study Year

Country Ref #




SCr % with DM

Results P value



RR (95% CI)102


Adults with mixed


(Median 12 wk)


dose atorvastatin, rosuvastatin, or simvastatin


or simvastatin

1895 (1911) nd 19–26 AEs leading to

study discontinuation

9% [4%] -- ≤0.05

Fenofibric acid +

atorvastatin Atorvastatin 11%

[3%] -- ≤0.05

Fenofibric acid + 10

mg/d rosuvastatin

10 mg/d Rosuvastati

n 10% [4%] -- ≤0.05


mg/d rosuvastatin

20 mg/d Rosuvastati

n 10% [5%] -- ≤0.05

Wiklund 1993 Sweden & Finland 46


erolemia 12 wk


Placebo

75 (75)

73 (73)

nd nd Left the study

because of clinical adverse events

4 (5%) [3 (4%)]

1.30 (0.30, 5.60) nd

Pravastatin 70 (70) 4 (5%) [2 (3%)]

1.87 (0.35, 9.88) nd

Gemfibrozil 72 (72) 4 (5%) [4 (6%)]

0.96 (0.25, 3.69) nd

Roth 2010 US47


erolemia and


12 wk (8 wk)


Simvastatin

118 (118)

119 (119) nd

22 (16)

AEs leading to discontinuations

6 (5%) [7 (6%)]

0.86 (0.30, 2.50) nd

10mg rosuvastatin + fenofibric acid

119 (119) 19 (16)

3 (3%)) [7 (6%)]

0.43 (0.11, 1.62) nd


118 (118) 23 (16)

4 (3%) [7 (6%)]

0.58 (0.17, 1.92) nd


55

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)102

Jones 2010 US49

Adults with mixed

dyslipidemia 16 wk

(12 wk)

Fenofibric acid +



and ezetimibe

272 (272) 270 (271) nd 20 (23)

AEs leading to discontinuations

16 (6%) [17 (6%)]

0.93 (0.48, 1.81) nd

Farnier 2010 EU50

Adults with mixed

dyslipidemia 12 wk

(12 wk) Fenofibrate + pravastatin Pravastatin 123 (123) 125 (125)

SCr 84.2 (85.5) µmol/L

26 (29)

Discontinued due to AE

5 (4%) [5 (4%)]

1.02 (0.30, 3.42) nd


Adults with mixed

hyperlipidemia

12 wk (12 wk)


and fenofibrate


183 (183)

184 (184) Median SCr 1.1 (1.1)

mg/dL

12 (6)

Discontinued owing to AEs

5 (3%) [5 (3%)]

1.01 (0.30, 3.41) nd

Discontinued owing to drug-

related AEs 4 (2%) [3 (2%)]

1.34 (0.30, 5.91) nd

Discontinued owing to SAEs

0 (0%) [0 (0%)] -- nd

Discontinued owing to drug-related SAEs

0 (0%) [0 (0%)] -- nd


mg/dL

12 (9)


5 (3%) [6 (3%)]

0.84 (0.26, 2.70) nd


related AEs 4 (2%) [6 (2%)]

0.67 (0.19, 2.34) nd


0 (0%) [1 (1%)] -- nd


0 (0%) [1 (1%)] -- nd

56

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)102


mg/dL

12 (10)


5 (3%) [1 (2%)]

1.64 (0.20, 13.76) nd


related AEs 4 (2%) [0 (0%)] -- nd


0 (0%) [1 (2%)] -- nd


0 (0%) [0 (0%)] -- nd

Davidson 2009 US52


12 wk (12 wk)


Atorvastatin 73 (73)

74 (74) SCr 1.0 (0.9)

mg/dL nd

Total treatment-emergent AEs

causing discontinuation

4 (5%) [5 (7%)]

0.81 (0.23, 2.90) nd

Fenofibrate 73 (73) 4 (5%) [8 (11%)]

0.50 (0.16, 1.59) nd

ACCORD 2010 US & Canada56

Patients with Type 2 DM at high risk

for CVD

5 y (5 y)

Simvastatin +fenofibrate

Simvastatin + placebo

2765 (2765)

2753 (2753)

SCr 0.9 (0.9)

mg/dL 100

(100) Discontinuation

due to a decrease in eGFR

66 (2%) [30 (1%)]

2.19 (1.43, 3.36) nd




and 52% without CAD

at entry

1 y


Atorvastatin

135 (135)

134 (134) nd 100 (100)

Withdrawn because of side

effects

1 (1%) [1 (1%)]

0.99 (0.06, 15.71) nd

Simvastatin + gemfibrozil 136 (136) 7 (5%)

[1 (1%)] 6.95

(0.87, 55.71) nd

Simvastatin + ciprofibrate 134 (134) 3 (2%)

[1 (1%)] 2.98

(0.31, 28.27) nd

Pravastatin + ciprofibrate 135 (135) 1 (1%)

[1 (1%)] 0.99

(0.06, 15.71) nd

57

Supplemental Table 25: Patients on statin + fibrate therapy with increased ALT or AST Study Year

Country Ref #




SCr % with DM

Results P value



RR (95% CI)103


Adults with mixed


(Median 12 wk)

Fenofibric acid 135mg + low-dose


or simvastatin

Atorvastatin, rosuvastatin, or simvastatin

1895 (1911) nd 19–26 ALT or AST >3xULN at 2 consecutive

visits

0–3% [0–2%] -- ≤0.001

Fenofibric acid

0–3% [0–4%] -- NS

Roth 2010 US47


erolemia and


12 wk (8 wk)


acid

Simvastatin

117 (118)

114 (119)

nd

22 (16)

ALT >3xULN,

consecutive

0 (0%) [0 (0%)] -- nd


acid 118 (119) 19

(16) 1 (1%)) [0 (0%)] -- nd


acid 115 (118) 23

(16) 2 (2%) [0 (0%)] -- nd


acid

Simvastatin

117 (118)

114 (119)

22 (16)

ALT >5xULN

2 (2%) [0 (0%)] -- nd


acid 118 (119) 19

(16) 0 (0%) [0 (0%)] -- nd


acid 115 (118) 23

(16) 1 (1%) [0 (0%)] -- nd


58

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)103


acid

Simvastatin

117 (118)

114 (119)

22 (16)

AST >3xULN,

consecutive

0 (0%) [0 (0%)] -- nd


acid 118 (119) 19

(16) 0 (0%) [0 (0%)] -- nd


acid 115 (118) 23

(16) 1 (1%) [0 (0%)] -- nd


Adults with mixed

dyslipidemia 2 y

(2 y)



or atorvastatin

Fenofibric acid

106 (106)

105 (105)

nd 100 (100)

ALT or AST >3xULN,

consecutive

2 (2%) [2 (2%)]

0.99 (0.14, 6.90) nd

Low dose statin 105 (105) 2 (2%)

[0 (0%)] -- nd


[0 (0%)] -- nd

Fenofibric acid+

moderate dose


or atorvastatin

Fenofibric acid

110 (110)

105 (105) 1 (1%) [2 (2%)]

0.48 (0.04, 5.19) nd


[0 (0%)] -- nd


[0 (0%)] -- nd

59

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)103

Jones 2010 US49

Adults with mixed

dyslipidemia 16 wk

(12 wk)

Fenofibric acid +

atorvastatin and

ezetimibe


and ezetimibe 272 (272) 270 (271) nd 20

(23)

ALT or AST >3xULN,

consecutiveor >5xULN

14 (5%) [4 (1%)]

3.47 (1.16, 10.42) NS

Farnier 2010 EU50

Adults with mixed

dyslipidemia 12 wk

(12 wk) Fenofibrate


26 (29)

Increased AST

<3xULN 3 (2%) [0 (0%)] -- nd


Adults with mixed

hyperlipidemia

12 wk (12 wk)


and fenofibrate


183 (183)

184 (184) Median SCr 1.1 (1.1)

mg/dL

12 (6)

ALT or AST ≥3x at 2

weekly visits between

weeks 11-13

5 (3%) [0 (0%)] -- nd


mg/dL

12 (9)

5 (3%) [6 (3%)]

0.84 (0.26, 2.70) nd


mg/dL

12 (10)

5 (3%) [0 (0%)] -- nd

60

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)103



for CVD

5 y (5 y)



2765 (2765)

2753 (2753)

SCr 0.9 (0.9)

mg/dL 100

(100) ALT >3xULN 52 (2%) [40 (1%)]

1.29 (0.86, 1.95) nd




and 52% without CAD

at entry

1 y

Statin + fibrate

(pravastatin or

simvastatin + gemfibrozil

or ciprofibrate)

Atorvastatin 540 (540) 134 (134) nd 100 (100) AST>3xULN 7 (1.3%)

[0 (0%)] -- nd

61

Supplemental Table 26: Patients on statin + fibrate therapy with increased CK Study Year

Country Ref #




SCr % with DM

Results P value



RR (95% CI)104


Adults with mixed


(Median 12 wk)

Fenofibric + low dose

atorvastatin, rosuvastatin, or simvastatin


or simvastatin

1895 (1911) nd 19–26 CK 5x or 10xULN

0–2% [0–2%] -- nd

Fenofibric acid

0–2% [0%] -- nd



erolemia 12 wk


Placebo

75 (75)

73 (73)

nd nd CK

increased to 4x baseline

at least once

4 (5%) [1 (1%)]

3.89 (0.45, 34.01) nd

Pravastatin 70 (70) 4 (5%) [1 (1%)]

3.73 (0.43, 32.60) nd

Gemfibrozil 72 (72) 4 (5%) [2 (3%)]

1.92 (0.36, 10.16) nd

Roth 2010 US47


erolemia and


12 wk (8 wk)


Simvastatin

118 (118)

119 (119)

nd

22 (16)

CK >5x ULN

0 (0%) [0 (0%)] -- nd


119 (119) 19 (16)

0 (0%) [0 (0%)] -- nd


118 (118) 23 (16)

2 (2%) [0 (0%)] -- nd


118 (118)

119 (119)

22 (16)

CK >10x ULN

0 (0%) [0 (0%)] -- nd


119 (119) 19 (16)

0 (0%) [0 (0%)] -- nd


118 (118) 23 (16)

1 (1%) [0 (0%)] -- nd


62

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)104


Adults with mixed

dyslipidemia 2 y

(2 y)



or atorvastatin

Fenofibric acid

106 (106)

105 (105)

nd 100 (100)

CK >5x ULN

1 (1%) [0 (0%)] -- nd


[0 (0%)] -- nd


[0 (0%)] -- nd

Fenofibric acid+

moderate dose


or atorvastatin

Fenofibric acid

110 (110)

105 (105) 0 (0%) [0 (0%)] -- nd


[0 (0%)] -- nd


[0 (0%)] -- nd



or atorvastatin

Fenofibric acid

106 (106)

105 (105)

CK >10x ULN

1 (1%) [0 (0%)] -- nd


[0 (0%)] -- nd


[0 (0%)] -- nd

Fenofibric acid+

moderate dose


or atorvastatin

Fenofibric acid

110 (110)

105 (105) 0 (0%) [0 (0%)] -- nd


[0 (0%)] -- nd

63

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)104


[0 (0%)] -- nd

Jones 2010 US49

Adults with mixed

dyslipidemia 16 wk

(12 wk)

Fenofibric acid +



and ezetimibe

272 (272) 270 (271) nd 20 (23)

CK >10x or >5x ULN

1 (0.3%) [3 (1%)]

0.33 (0.03, 3.16) NS

Farnier 2010 EU50

Adults with mixed

dyslipidemia 12 wk

(12 wk) Fenofibrate + pravastatin Pravastatin 123 (123) 125 (125)

SCr 84.2 (85.5) µmol/L

26 (29)

CK ≥10xULN

with or without

muscular symptoms

0 (0%) [1 (1%)] -- nd



for CVD

5 y (5 y)



2765 (2765)

2753 (2753)

SCr 0.9 (0.9)

mg/dL 100

(100) CK

>10xULN 10 (0.4%) [9 (0.3%)]

1.11 (0.45, 2.72) nd

64

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)104




and 52% without CAD

at entry

1 y

Statin + fibrate

(pravastatin or simvastatin + gemfibrozil

or ciprofibrate)

Atorvastatin 540 (540) 134 (134) nd 100 (100)

CK >5xULN in

simvastatin + gemfibrozil

group

3 (1%) [0 (0%)] -- nd

65

Supplemental Table 27: Patients on statin + fibrate therapy with increased serum creatinine Study Year

Country Ref #




SCr % with DM

Results P value



RR (95% CI)105


Adults with mixed


(Median 12 wk)

Fenofibric acid 135mg + low-dose


or simvastatin

Atorvastatin, rosuvastatin, or simvastatin

1895 (1911) nd 19–26 ↑SCr ≥50% and >ULN

2–4% [0–2%] -- <0.05

Fenofibric acid

2–4% [1–3%] -- NS

Roth 2010 US47


erolemia and


12 wk (8 wk)


acid

Simvastatin

117 (118)

115 (119) nd

22 (16)

↑SCr ≥50% and >ULN

1 (1%) [0 (0%)] -- nd


acid 118 (119) 19

(16) 3 (3%) [0 (0%)] -- nd


acid 115 (118) 23

(16) 2 (2%) [0 (0%)] -- nd


acid

Simvastatin

117 (118)

115 (119) nd

22 (16)

↑SCr ≥100%

0 (0%) [0 (0%)] -- nd


acid 118 (119) 19

(16) 1 (1%) [0 (0%)] -- nd


acid 115 (118) 23

(16) 0 (0%) [0 (0%)] -- nd


66

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)105


Adults with mixed

dyslipidemia 2 y

(2 y)



or atorvastatin

Fenofibric acid

106 (106)

105 (105)

nd 100 (100)

SCr >1.5 x baseline and

>ULN

4 (4%) [6 (6%)]

0.66 (0.19, 2.27) nd


[2 (2%)] 1.98

(0.37, 110.59) nd


[0 (0%)] -- nd

Fenofibric acid+

moderate dose


or atorvastatin

Fenofibric acid

110 (110)

105 (105) 4 (4%) [6 (6%)]

0.64 (0.18, 2.19) nd


[2 (2%)] 1.91

(0.36, 10.20) nd


[0 (0%)] -- nd



or atorvastatin

Fenofibric acid

106 (106)

105 (105)

SCr >2 x baseline

1 (1%) [0 (0%)] -- nd


[0 (0%)] -- nd


[0 (0%)] -- nd

Fenofibric acid+

moderate dose


or

Fenofibric acid

110 (110)

105 (105) 0 (0%) [0 (0%)] -- nd


[0 (0%)] -- nd

67

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)105

atorvastatin


[0 (0%)] -- nd

Jones 2010 US49

Adults with mixed

dyslipidemia 16 wk

(12 wk)

Fenofibric acid +

atorvastatin and

ezetimibe


and ezetimibe 267 (272) 267 (271) nd 20

(23)

↑SCr ≥50% and >1X

ULN 1 (0.4%) [1 (0.4%)]

1.00 (0.06, 15.91) nd

↑SCr ≥100%

1 (0.4%) [1 (0.4%)]

1.00 (0.06, 15.91) nd

SCr > 2 mg/dL

2 (1%) [0 (0%)] -- nd

Farnier 2010 EU50

Adults with mixed

dyslipidemia 12 wk

(12 wk) Fenofibrate


26 (29) ↓CrCl 3 (2%)

[1 (1%)] 3.05

(0.32, 28.91) nd

68

Supplemental Table 28: Patients receiving statin + fibrate therapy reporting rhabdomyolysis Study Year

Country Ref #




SCr % with DM

Results P value



RR (95% CI)106

Law 2006 UK&US57

Systematic review 1980-

2005: 2 cohort studies

1980-2005

Cerivastatin + gemfibrozil Cerivastatin

nd nd nd nd

Incidence rate of

rhadbdomyolysis (95%

CI) per 100,000

person-yr

10,300 (3800-22,500)

[46 (13-120)]

-- nd Any other statin +

gemfibrozil Any other

statin 35 (1-194)

[3.4 (1.6-6.5)]

Same systematic

review, 1980-2005, but data are

physician reports to

FDA Adverse Events

Reporting System

Cerivastatin + gemfibrozil Cerivastatin

nd nd nd nd

15,000 (13,000-17,000)

[21 (19-25)]

-- nd Any other statin +

gemfibrozil Any other

statin 21 (17-25)

[0.70 (0.62-0.79)]


Adults with mixed


(Median 12 wk)



or simvastatin


or simvastatin

1895 (1911) nd 19-26 Rhabdomyolysis

0 (0%) [0 (0%)] -- nd

Fenofibric acid +

atorvastatin Atorvastatin 0 (0%)

[0 (0%)] -- nd


mg/d rosuvastatin

10 mg/d Rosuvastati

n 0 (0%) [0 (0%)] -- nd

106 All RRs and CIs were calculated by ERT

69

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)106


mg/d rosuvastatin

20 mg/d Rosuvastati

n 0 (0%) [0 (0%)] -- nd



erolemia 12 wk

(12 wk) Pravastatin

+ gemfibrozil

Placebo

75 (75)

73 (73)

nd nd Rhabdomyolysis

0 (0%) [0 (0%)] -- nd

Pravastatin 70 (70) 0 (0%) [0 (0%)] -- nd

Gemfibrozil 72 (72) 0 (0%) [0 (0%)] -- nd

Roth 2010 US47


erolemia and


12 wk (8 wk)


acid

Simvastatin

118 (118)

119 (119) nd

22 (16)

Rhabdomyolysis

0 (0%) [0 (0%)] -- nd


acid 119 (119) 19

(16) 0 (0%) [0 (0%)] -- nd


acid 118 (118) 23

(16) 0 (0%) [0 (0%)] -- nd


Adults with mixed

dyslipidemia 2 y

(2 y)

Fenofibric acid + low-


or atorvastatin

Fenofibric acid

106 (106)

105 (105)

nd 100 (100)

Rhabdomyolysis

0 (0%) [0 (0%)] -- nd


[0 (0%)] -- nd

Moderate-dose statin

only 107 (107) 0 (0%)

[0 (0%)] -- nd

Fenofibric acid +

moderate-dose


or atorvastatin

Fenofibric acid

110 (110)

105 (105) 0 (0%) [0 (0%)] -- nd


[0 (0%)] -- nd

Moderate dose statin

only 107 (107) 0 (0%)

[0 (0%)] -- nd

Jones 2010 US49

Adults with mixed

dyslipidemia 16 wk

(12 wk)

Fenofibric acid +

atorvastatin and

ezetimibe


and ezetimibe

272 (272) 270 (271) nd 20 (23)

Rhabdomyolysis

0 (0%) [0 (0%)] -- nd

70

Study Year Country

Ref # Population

Duration Outcome



SCr % with DM

Results P value



RR (95% CI)106

Farnier 2010 EU 50

Adults with mixed

dyslipidemia 12 wk

(12 wk) Fenofibrate

+ pravastatin Pravastatin 123 (123) 125 (125) SCr 84.2

(8.5) µmol/L

26 (29)

Rhabdomyolysis

0 (0%) [0 (0%)] -- nd


Adults with mixed

hyperlipidemia

12 wk (12 wk)


and fenofibrate


183 (183)

184 (184) Median SCr 1.1 (1.1)

mg/dL

12 (6)

Rhabdomyolysis

0 (0%) [0 (0%)] -- nd


mg/dL

12 (9)

0 (0%) [0 (0%)] -- nd


mg/dL

12 (10)

0 (0%) [0 (0%)] -- nd

Davidson 2009 US52


12 wk (12 wk)


Atorvastatin

73 (73)

74 (74) SCr 1.0 (0.9)

mg/dL nd Rhabdomyolysis

0 (0%) [0 (0%)] -- nd


mg/dL 0 (0%) [0 (0%)] -- nd

71

Supplemental Table 29: Summary table of RCTs of statin vs. placebo in kidney transplant patients [categorical outcomes]


Country Ref #

Duration Outcome



P value Quality

Intervention Control Intervention Control GFR or SCr

DM (%)



RR/OR/HR (95% CI) (mmol/L)

Mortality

All-cause death ALERT Holdaas 2003 EU & Canada58


(1050) 1052

(1052)

CKD T SCr 147 (143)

µmol/L

19 (19)

6.4 (6.5)

4.1 (4.1)

1.3 (1.4)

2.2 (2.2)

143 (14%) [138 (13%)]

RR 1.02 (0.81, 1.30) NS Good

Non-CV deaths 77 (7%) [65 (6%)]

RR 1.20 (0.86, 1.67) NS Good

All-cause mortality

ALERT- Extension107 Holdaas 2005 EU & Canada59

7 y (7 y108) Fluvastatin Placebo 819

(819) 833

(833)

CKD T SCr 144 (139)

µmol/L

17 (16)

6.4 (6.5)

4.1 (4.1)

1.3 (1.4)

2.2 (2.2)

194 (19%) [189 (18%)]

RR 1.02 (0.83, 1.24) NS Fair

Non-CV death 101 (10%) [90 (9%)]

RR 1.12 (0.84, 1.49) NS Fair

CV mortality

Cardiac death ALERT Holdaas 2003 EU & Canada58 5 y

(5 y) Fluvastatin Placebo

1050 (1050)

1052 (1052)

CKD T SCr 147 (143)

µmol/L

19 (19)

6.4 (6.5)

4.1 (4.1)

1.3 (1.4)

2.2 (2.2)

36 (3%) [54 (5%)]

RR 0.62 (0.40, 0.96) 0.031 Good

Cardiac death in patients started on statin <4.5 y after transplant

ALERT Holdaas 2005 EU & Canada60

522 (522)

521 (521)

CKD T SCr 144 (142)

µmol/L

21 (20)

6.5 (6.4)

4.2 (4.1)

1.3 (1.3)

2.3 (2.3) nd RR 0.61

(0.29,1.26) NS Good

CV events Cardiac death, definite or probable nonfatal MI, CABG/PCI (primary)



(1050) 1052

(1052)

CKD T SCr 147 (143)

µmol/L

19 (19)

6.4 (6.5)

4.1 (4.1)

1.3 (1.4)

2.2 (2.2)

112 (11%) [134 (13%)]

RR 0.83 (0.64, 1.06) NS Good

Cardiac death or definite or probable non-fatal MI

79 (8%) [105 (10%)]

RR 0.72 (0.54, 0.97) 0.032 Good

107 All participants, regardless of the original treatment assignment, received open label fluvastatin. 108 The patients who completed the core study were offered open-label fluvastatin and active follow-up. Data were collected on those patients who declined active therapy or follow-up at the end of the extension period.

72


Country Ref #

Duration Outcome



P value Quality


DM (%)




Cardiac death or definite non-fatal MI

70 (7%) [104 (10%)]

RR 0.65 (0.48, 0.88)

0.005109 Good

Definite non-fatal MI

46 (4%) [66 (6%)]

RR 0.68 (0.40, 1.00) 0.050 Good

CABG 25 (2%) [24 (2%)]

RR 1.03 (0.58, 1.81) NS Good

PCI 29 (3%) [37 (4%)]

RR 0.80 (0.49, 1.30) NS Good

Fatal or non-fatal cerebrovascular events

74 (7%) [63 (6%)]

RR 1.16 (0.83, 1.63) NS Good

Cardiac death or non-fatal MI in patients started on statin <4.5 y after transplant



(522) 521

(521)

CKD T SCr 144 (142)

µmol/L

21 (20)

6.5 (6.4)

4.2 (4.1)

1.3 (1.3)

2.3 (2.3)

24 (5%) [48 (9%)]

RR 0.44 (0.26,0.74) 0.002 Good

Non-fatal MI in patients started on statin <4.5 y after transplant

16 (18) nd RR 0.44

(0.23, 0.84) 0.012 Good

Cardiac death, non-fatal MI, CABG, PCI (primary)

ALERT- Extension110 Holdaas 2005 EU & Canada59


(819) 833

(833)

CKD T SCr 144 (139)

µmol/L

17 (16)

6.5 (6.5)

4.1 (4.1)

1.3 (1.4)

2.3 (2.2)

137 (13%) [174 (17%)]

RR 0.79 (0.63, 0.99) 0.036 Fair

Cardiac death, non-fatal MI

95 (9%) [128 (12%)]

RR 0.71 (0.55, 0.93) 0.014 Fair

CABG/PCI 59 (6%) [88 (8%)]

RR 0.67 (0.48, 0.94) 0.019 Fair

109 These data are exploratory and merely show that it is easier to detect a significant reduction in some subgroups than in others. However, the overlapping 95% confidence intervals and negative interaction analysis indicate that there is no significance when individual subgroups (e.g. men and women) are compared with one another. The failure to achieve statistical significance in some subgroups is likely to reflect the low number of events and the low overall power of the study. 110 All participants, regardless of the original treatment assignment, received open label fluvastatin. 111 The patients who completed the core study were offered open-label fluvastatin and active follow-up. Data were collected on those patients who declined active therapy or follow-up at the end of the extension period.

73


Country Ref #

Duration Outcome



P value Quality


DM (%)




Fatal or non-fatal cerebrovascular events

93 (9%) [91 (9%)]

RR 1.01 (0.75, 1.35) NS Fair

CV event112 in patients with SLE (primary)

ALERT- Extension Norby 2009. EU & Canada61


(23) 10

(10)

SCr 133.5

(129.4) µmol/L

nd 6.4 (6.2)

4.0 (3.9)

1.4 (1.3)

2.2 (1.9)

3 (13%) [4 (40%)]

RR 26.6 (5.9, 119.4)

NS (0.064) Good

Cardiac death or definite MI in patients with DM

ALERT Jardine 2004 EU & Canada62

5 y (5 y) Fluvastatin Placebo nd nd nd

100 (100)

nd 4.1 (4.1) nd nd

25 (13%) [34 (17%)]

RR 0.71 (0.41, 1.21) nd Fair

Cardiac death or definite MI in patients without DM

0 (0) 45 (5%) [70 (8%)]

RR 0.62 (0.43, 0.91) nd Fair

Cardiac death or definite MI in patients with CHD

19 (19)

20 (20%) [24 (24%)]

RR 0.72 (0.39, 1.34) nd Fair

Cardiac death or definite MI in patients without CHD

19 (19)

50 (5%) [80 (8%)]

RR 0.63 (0.44, 0.89) nd Fair

Graft loss Graft loss or doubling of SCr



(1050) 1052

(1052)

CKD T SCr 147 (143)

µmol/L

19 (19)

6.4 (6.5)

4.1 (4.1)

1.3 (1.4)

2.2 (2.2)

183 (17%) [165 (16%)]

RR 1.10 (0.89, 1.36) NS Good

Graft loss 146 (14%) [137 (13%)]

RR 1.005 (0.835,

1.334)114 NS Good

Graft loss or doubling of SCr or death

276 (26%) [268 (26%)]

RR 1.02 (0.86, 1.21) NS Good

112 Nonfatal MI cardiac death and coronary intervention procedure 113 The patients who completed the core study were offered open-label fluvastatin and active follow-up. Data were collected on those patients who declined active therapy or follow-up at the end of the extension period. 114 Calculated by ERT.

74


Country Ref #

Duration Outcome



P value Quality


DM (%)




Graft loss in patients with moderate renal impairment ALERT

Fellstrom 2006 EU & Canada63

5 y (5 y) Fluvastatin Placebo

318 (318)

336 (336)

GFR<50 mL/min

19 (19) nd nd nd nd

91 (29%) [87 (26%)]

RR 1.11 (0.86, 1.42) NS Good

Graft loss in patients with severe renal impairment

45 (45)

49 (49)

GFR<30 mL/min

28 (62%) [25 (51%)]

RR 1.22 (0.85, 1.74) NS Good

Graft loss in all patients

ALERT Fellstrom 2006 EU & Canada63

5 y (5 y) Fluvastatin Placebo 1050 (1050) 1052

(1052) SCr 143 µmol/L

19 (19) 6.5 4.1 1.4 2.2 146 (14%)

137 (13%) RR 1.07

(0.86, 1.33) NS Good

First treated acute rejection (primary)

Holdaas 2001 EU64

3 mo (3 mo) Fluvastatin Placebo 182

(182) 182

(182) CKD T

SCr 160 umol/L

12 (14)

4.77 (4.74)

2.99 (2.96)

1.02 (1.02)

1.68 (1.55)

86 (47%) [87 (48%)]

RR 0.99 (0.80, 1.23) NS Good

First steroid-resistant acute rejection

38 (21%) [34 (19%)]

RR 1.12 (0.74, 1.69) NS Good

First biopsy-confirmed acute rejection

70 (39%) [75 (41%)]

RR 0.93 (0.72, 1.20) NS Good

Days to treated first acute rejection

19 [18] -- NS Good

Second acute rejection episode

18 (10%) [19 (10%)]

RR 0.95 (0.51, 1.75) NS Good

75


Country Ref #

Duration Outcome



P value Quality


DM (%)




Graft loss or death

12 (6.6%) [7 (3.8%)]

RR 1.71 (0.69, 4.26) NS Good

Biopsy-confirmed rejection, graft loss, or death

77 (42%) [80 [44%])

RR 0.96 (0.76, 1.22) NS Good

Severity of rejection- (BANFF I) Mild

26 (14%) [42 (23%)] --

NS (0.091)

Good

Severity of rejection- (BANFF II) Moderate

36 (20%) [27 (15%)] -- Good

Severity of rejection- (BANFF III) Severe

8 (4%) [6 (3%)] -- Good

76

Supplemental Table 30: Summary table of RCTs of statin vs. placebo in kidney transplant patients [continuous outcomes]

Outcome Author,

Year Country

Ref #

Duration Outcome



P value Quality Intervention Control Intervention Control GFR or

SCr DM (%)


(Control)

Final Intervention

(Control)

∆ Intervention

(Control) Net ∆

(95% CI)

Lipid levels

∆LDL, mmol/L115 ALERT

Holdaas 2003 EU & Canada58

6 wk (5 y)

Fluvastatin Placebo 1050 (1050)

1052 (1052)

CKD T SCr 147 (143)

µmol/L

19 (19)

4.1 (4.1)

3.1116 (4.0)

-1.0 (-0.1) -0.9 nd Good

5 y (5 y)

2.8117 (3.8)

-1.3 (-0.3) -1.0 nd Good


6 wk (5 y) 6.4

(6.5)

5.2118 (6.4)

-1.3 (-0.1) -1.2 nd Good

5 y (5 y)

4.9119 (6.0)

-1.5 (-0.5) -1.0 nd Good

∆LDL in patients with SLE, mmol/L

ALERT Norby 2009 EU & Canada61


(23) 10

(10) SCr 133.5 (129.4) µmol/L

nd

4.0 (3.9)

2.8 (nd)

29.2% (18.3, 40) -- nd Fair

∆Total cholesterol in patients with SLE, mmol/L

6.4 (6.2)

5.1 (nd)

19.6% (11.7, 27.5) -- nd Fair

Total cholesterol, mmol/L

Holdaas 2001 EU64

3 mo (3 mo) Fluvastatin Placebo nd

(182) nd

(182) CKD T 12 (14)

4.77 (4.74)

5.47 (6.08)

0.70 (1.34)

−0.73 (-1.08, -0.37) <0.001 Good

LDL cholesterol, mmol/L

2.99 (2.96)

3.06 (3.74)

0.07 (0.78)

−0.84 (−1.12, −0.56)

<0.001 Good

HDL cholesterol, mmol/L

1.02 (1.02)

1.40 (1.32)

0.38 (0.30)

0.08 (−0.03, 0.19) NS Good

Triglycerides, mmol/L

1.68 (1.55)

2.04 (2.24)

0.36 (0.69)

−0.30 (−0.57, −0.02)

0.034 Good

115 During the course of the study, 696 (66.3%) of the patients in the fluvastatin group achieved total cholesterol concentrations lower than 5·0 mmol/L, and 779 (74·2%) achieved an LDL cholesterol concentrations lower than 3.0 mmol/L, meeting recommended values for prevention of CHD. 116 Estimated from figure 117 Estimated from figure 118 Estimated from figure 119 Estimated from figure 120 The patients who completed the core study were offered open-label fluvastatin and active follow-up. Data were collected on those patients who declined active therapy or follow-up at the end of the extension period.

77

Supplemental Table 31: Evidence profile of RCTs examining the effect of statins vs. placebo in kidney transplant recipients


and study design

Total N (treatment)



across studies




Summary of findings

Quality of evidence for outcome

Qualitative and quantitative description of effect

Importance of outcome

Mortality 1 RCT (High)

2102 (1050)


(0) Sparse

(-1) Moderate No difference Critical

CV mortality 1 RCT (High)

2102 (1050)


(0) Sparse

(-1) Moderate Benefit from statins Critical

CV events 1 RCT (High)

2102 (1050)


(0) Sparse

(-1) Moderate Benefit from statins Critical

ESRD 0 RCTs -- -- -- -- -- -- -- Critical

Graft loss 2 RCTs (High)

2466 (1232)

No limitations (0)


(0) Direct

(0) None

(0) High No difference High


0 RCTs -- -- -- -- -- -- -- High


2 RCTs (High)

2466 (1232)

No limitations (0)

Important inconsistencies

(-1)


(-1) None

(0) Low Benefit from statins Moderate

Adverse events 2 RCTs (High)

2466 (1232) No difference Moderate

Total 2 RCTs (High)

2466 (1232)

Balance of potential benefits and harms: Benefit for CV events

Quality of overall evidence: Moderate

78

Supplemental Table 32: Summary table of RCTs of statins vs. placebo in children with CKD without DM [continuous outcomes]


Country Ref #

Duration Outcome



value Quality Intervention Control Intervention Control GFR or SCr DM

(%) Baseline


Final Intervention

(Control)

∆ Intervention

(Control) Net ∆

(95% CI)

Lipid levels ∆Total cholesterol, mmol/L Mackie

201065 Australia

2 mo (2 mo)

Atorvastatin 10 mg/d Placebo 8

(8) 8

(8) SCr 293 (284)

µmol/L nd

5.1 (4.9)

3.8 (5.0)

-1.3 (0.1) -1.2 <0.00

1 Fair

∆LDL, mmol/L 3.1 (3.0)

1.9 (3.1)

-1.1 (0.2) -0.9 <0.00

1 Fair

∆Triglycerides, mmol/L

1.2 (1.2)

1.2 (1.5)

-0.4 (+0.3) -0.1 nd Poor

79

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Documents

KDIGO CLINICAL PRACTICE GUIDELINE FOR LIPID … · Suppl Table 1: Summary table of RCT examining the effect of exercise in CKD 5HD patients [continuous outcomes] Suppl Table 2: Summary